Substituted beta carbolines

ABSTRACT

The subject matter of the present invention is directed to novel substituted beta-carbolines, and specifically compounds of the formula I,  
                 
which are suitable for the production of pharmaceuticals for the prophylaxis and therapy of disorders in whose course an increased activity of IκB kinase is involved.

This application claims benefit of priority to EP Application no.00105514.4, filed Mar. 15, 2000, and EP Application no. 00125169.3,filed Nov. 18, 2000, both of which are incorporated herein by reference.

The present invention relates to novel substituted beta-carbolines, aprocess for their preparation and use thereof as pharmaceuticals.

Art related to the present invention includes U.S. Pat. Nos. 4,631,149and 5,604,236. U.S. Pat. No. 4,631,149 discloses beta-carbolines usefulas antiviral, antibacterial and antitumor agents. U.S. Pat. No.5,604,236 discloses beta-carboline derivatives containing an acidicgroup, useful as thromboxane syntheses inhibitors.

NFkB is a heterodimeric transcription factor which can activate a largenumber of genes which code, inter alia, for proinflammatory cytokinessuch as IL-1, IL-2, TNFα or IL-6. NFkB is present in the cytosol ofcells, building a complex with its naturally occurring inhibitor IkB.The stimulation of cells, for example by cytokines, leads to thephosphorylation and subsequent proteolytic degradation of IkB. Thisproteolytic degradation leads to the activation of NFkB, whichsubsequently migrates into the nucleus of the cell and there activates alarge number of proinflammatory genes.

In disorders such as rheumatoid arthritis (in the case of inflammation),osteoarthritis, asthma, cardiac infarct, Alzheimer's disease oratherosclerosis, NFkB is activated beyond the normal extent. Inhibitionof NFkB is also of benefit in cancer therapy, since it is employed therefor the reinforcement of the cytostatic therapy. It has been shown thatpharmaceuticals such as glucocorticoids, salicylates or gold salts,which are employed in rheumatic therapy, intervene in an inhibitorymanner at various points in the NFkB-activating signal chain orinterfere directly with the transcription of the genes.

The first step in the signal cascade mentioned is the degradation ofIkB. This phosphorylation is regulated by the specific IkB kinase. Todate, no inhibitors are known which specifically inhibit IkB kinase.

In the attempt to obtain active compounds for the treatment ofrheumatoid arthritis (in the case of inflammation), osteoarthritis,asthma, cardiac infarct, Alzheimer's disease, carcinomatous disorders(potentiation of cytotoxic therapies) or atherosclerosis, the inventorshave surprisingly discovered that the benzimidazoles of the presentinvention are strong and very specific inhibitors of IkB kinase.

The invention therefore relates to the compounds of the formula I

and/or a stereoisomeric form of the compounds of the formula I and/or aphysiologically tolerable salt of the compounds of the formula I,where B₆, B₇, B₈ and B₉ are independently selected from the groupconsisting of carbon atom and nitrogen atom, where B₆, B₇, B₈ and B₉together comprise no more than two nitrogen atoms; wherein

-   in case a)    -   the substituents R¹, R² and R³ may be independently chosen from:    -   1.1. hydrogen atom,    -   1.2. halogen,    -   1.3. —CN,    -   1.4. —COOH,    -   1.5. —NO₂,    -   1.6. —NH₂,    -   1.7. —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-        to penta-substituted by substituents independently chosen from:        -   1.7.1 phenyl, which is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            halogen or —O—-(C₁-C₄)-alkyl,        -   1.7.2 halogen,        -   1.7.3 —NH₂,        -   1.7.4 —OH,        -   1.7.5 —COOR¹⁶, wherein R¹⁶ is hydrogen atom or            —(C₁-C₁₀)-alkyl,        -   1.7.6 —NO₂,        -   1.7.7 —S(O)—R¹⁴, wherein y is zero, 1 or 2, R¹⁴ is            —(C₁-C₁₀)-alkyl, phenyl, which phenyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those defined under 1.7.1 to 1.7.11, amino or            —N(R¹³)₂,            -   wherein R¹³ is independently of one another chosen from                hydrogen atom, phenyl, —(C₁-C₁₀)-alkyl,                —C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl,                —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,                —C(O)—O—(C₁-C₇)-alkyl,            -   —S(O)—R¹⁴, wherein R¹⁴ and y are as defined above,            -   and wherein the R¹³ alkyl or phenyl groups in each case                are unsubstituted or mono- to penta-substituted by                substituents independently chosen from those as defined                under 1.7.1 to 1.7.11, or            -   R¹³ together with the nitrogen atom to which it is                bonded may be independently chosen to form a heterocycle                having 5 to 7 ring atoms,        -   1.7.8 —O-phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted independently of one another as defined            under 1.7.1 to 1.7.11,        -   1.7.9 a radical selected from pyrrolidine,            tetrahydropyridine, piperidine, piperazine, imidazoline,            pyrazolidine, furan, morpholine, pyridine, pyridazine,            pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline,            isothiazolidine, 2-isothiazoline, thiophene or            thiomorpholine,        -   1.7.10 —(C₃-C₇)-cycloalkyl or        -   1.7.11 ═O,    -   1.8. —N(R¹³)₂, wherein R¹³ is as defined in 1.7.7 above,    -   1.9. —NH—C(O)—R¹⁵, wherein R¹⁵ is        -   1.9.1 a radical selected from pyrrolidine,            tetrahydropyridine, piperidine, piperazine, imidazoline,            pyrazolidine, furan, morpholine, pyridine, pyridazine,            pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline,            isothiazolidine, 2-isothiazoline, thiophene or            thiomorpholine,            -   wherein said radical is unsubstituted or mono- to                penta-substituted by substituents independently chosen                from those as defined under 1.7.1 to 1.7.11 above, by                —CF₃, by benzyl or by —(C₁-C₁₀)-alkyl, wherein the                —(C₁-C₁₀)-alkyl is mono to tri-substituted by                substituents independently chosen from those as defined                under 1.7.1 to 1.7.11 above,        -   1.9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 1.7.1 to 1.7.11 above or            by —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 1.7.1 to 1.7.11 above,        -   1.9.3 —(C₃-C₇)-cycloalkyl,        -   1.9.4 —N(R¹³)₂, wherein R¹³ is as defined in 1.7.7 above, or        -   1.9.5 phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11 above, by            —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl,            wherein alkyl is mono to tri-substituted by substituents            independently chosen from those as defined under 1.7.1 to            1.7.11 above, or by two substituents of said phenyl which            form a dioxolan ring,    -   1.10. —S(O)_(y)—R¹⁴, wherein R¹⁴ and y are as defined in 1.7.7        above,    -   1.11. —C(O)—R², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein        alkyl or phenyl are unsubstituted or mono- to penta-substituted        by substituents independently chosen from those as defined under        1.7.1 to 1.7.11 above,    -   1.12. —C(O)—O—R², wherein R¹² is as defined in 1.11. above,        1.13. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-        to penta-substituted by substituents independently chosen from        those as defined under 1.7.1 to 1.7.11 above,    -   1.14. —O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl,    -   1.15. —O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl,    -   1.16. —(C₁-C₄)-alkyl-N(R³)₂, wherein R¹³ is as defined in 1.7.7        above    -   1.17. —CF₃ or    -   1.18. —CF₂—CF₃,-   R⁴ is 1. —(C₁-C₁₀)-alkyl, wherein alkyl is mono- to    penta-substituted by substituents independently chosen from those as    defined under 1.7.1 to 1.7.11 above,    -   2. —CF₃,    -   3. —CF₂—CF₃,    -   4. —CN,    -   5. —S(O)_(y)—R¹⁴, wherein R¹⁴ and y are as defined in 1.7.7        above,    -   6. —NH₂,    -   7. —O—(C₁-C₁₀)-alkyl, wherein alkyl is mono- to        penta-substituted by substituents independently chosen from        -   7.1 phenyl, which is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            halogen or —O—(C₁-C₄)-alkyl,        -   7.2 halogen,        -   7.3 —NH₂,        -   7.4 —OH,        -   7.5 —COOR¹⁶, wherein R¹⁶ is hydrogen atom or            —(C₁-C₁₀)-alkyl,        -   7.6 —NO₂,        -   7.7 —S(O)—R¹⁴, wherein y is zero, 1 or 2, R¹⁴ is            —(C₁-C₁₀)-alkyl, phenyl, which phenyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 1.7.1 to 1.7.11, amino or            —N(R¹³)₂,            -   wherein R¹³ is independently of one another chosen from                hydrogen atom, phenyl, —(C₁-C₁₀)-alkyl,                —C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl,                —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,                —C(O)—O—(C₁-C₇)-alkyl, —S(O)—R⁴, wherein R¹⁴ and y are                defined as in 7.7,            -   and wherein the R¹³ alkyl or phenyl groups in each case                are unsubstituted or mono- to penta-substituted by                substituents independently chosen from those as defined                under 1.7.1 to 1.7.11 above, or            -   R¹³ together with the nitrogen atom to which it is                bonded form a heterocycle having 5 to 7 ring atoms,        -   7.8 —O-phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11 above,        -   7.9 a radical selected from pyrrolidine, tetrahydropyridine,            piperidine, piperazine, imidazoline, pyrazolidine, furan,            morpholine, pyridine, pyridazine, pyrazine, oxolan,            imidazoline, isoxazolidine, thiophene, 2-isoxazoline,            isothiazolidine, 2-isothiazoline, or thiomorpholine,        -   7.10 —(C₃-C₇)-cycloalkyl or        -   7.11 ═O,    -   8. —N(R¹⁷)₂, wherein R¹⁷ is independently of one another chosen        from hydrogen atom, phenyl, —(C₁-C₁₀)-alkyl, —C(O)-phenyl,        —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—(C₁-C₁₀)-alkyl, —C(O)—O-phenyl,        —C(O)—NH-phenyl, —C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R⁴, wherein        R¹⁴ and y are as defined as in 7.7 above,        -   and wherein alkyl or phenyl in each case are unsubstituted            or mono- to penta-substituted independently of one another            as defined under 1.7.1 to 1.7.11 above, or        -   R¹⁷ together with the nitrogen atom to which it is bonded            form a heterocycle having 5 to 7 ring atoms,    -   9. —NH—C(O)—R¹⁵, wherein R¹⁵ is        -   9.1 a radical selected from pyrrolidine, tetrahydropyridine,            piperidine, piperazine, imidazoline, pyrazolidine, furan,            morpholine, pyridine, pyridazine, pyrazine, oxolan,            imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine,            2-isothiazoline, thiophene or thiomorpholine,            -   wherein said radical is unsubstituted or mono- to                penta-substituted by substituents independently chosen                from those as defined under 1.7.1 to 1.7.11 above, —CF₃,                benzyl or by —(C₁-C₁₀)-alkyl, wherein alkyl is mono to                tri-substituted by substituents independently chosen                from those as, defined under 1.7.1 to 1.7.11 above,        -   9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11 above or by            —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-            to penta-substituted by substituents independently chosen            from those as defined under 1.7.1 to 1.7.11 above,        -   9.3 —(C₃-C₇)-cycloalkyl,        -   9.4 —N(R³)₂, wherein R¹³ is as defined in 1.7.7 above            provided that            -   —N(R¹³)₂ is not —NH₂, or        -   9.5 phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11 above, by            —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl,            wherein alkyl is mono to tri-substituted by substituents            independently chosen from those as defined under 1.7.1 to            1.7.11 above, or by two substituents of the phenyl radical            which form a dioxolan ring    -   10. —C(O)—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein        phenyl or alkyl are mono- to penta-substituted by substituents        independently chosen from those as defined under 1.7.1 to 1.7.11        above,    -   11. —C(O)—O—R¹², wherein R¹² is as defined in 10, above,    -   12. —O—(C. —C₆)-alkyl-O—(C₁-C₆)-alkyl,    -   13. —O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl or    -   14. —(C₁-C₄)-alkyl-N(R¹³)₂, wherein R¹³ is as defined in 1.7.7        above,-   R⁵ is 1. a hydrogen atom,    -   2. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- to        penta-substituted by substituents independently chosen from        those as defined under 1.7.1 to 1.7.4 above,    -   3. —C(O)—R⁹, wherein R⁹ is        -   —NH₂, —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 7.1 to 7.4, or —N(R¹³)₂,            wherein R¹³ is as defined in 1.7.7 above, or    -   4. —S(O)₂—R⁹, wherein R⁹ is as defined in 3. above, or-   R⁴ and R⁵ together with the atom to which they are bonded form a    heterocycle, or-   R³ and R⁵ together with the atom to which they are bonded form a    heterocycle containing an additional oxygen atom in the ring and-   R⁶, R⁷ and R⁸ independently of one another are chosen from hydrogen    atom or methyl, or-   in case b)    -   the substituents R¹, R² and R⁴ may be independently chosen as        defined under 1.1 to 1.18 in case a) above,-   R³ is 1. —CF₃,    -   2. —CF₂—CF₃,    -   3. —CN,    -   4. —COOH,    -   5. —NO₂,    -   6. —NH₂,    -   7. —O—(C₁-C₁₀)-alkyl, wherein alkyl is mono- to penta        substituted by substituents independently chosen from        -   7.1 phenyl, which is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            halogen or —O—(C₁-C₄)-alkyl,        -   7.2 halogen,        -   7.3 —NH₂,        -   7.4 —OH,        -   7.5 —COOR⁶, wherein R¹⁶ is hydogen atom or —(C₁-C₁₀)-alkyl,        -   7.6 —NO₂,        -   7.7 —S(O)—R¹⁴, wherein y is zero, 1 or 2, R¹⁴ is            —(C₁-C₁₀)-alkyl, phenyl, which phenyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 1.7.1 to 1.7.11, amino or            —N(R¹³)₂,            -   wherein R¹³ is independently of one another chosen from                hydrogen atom, phenyl, —(C₁-C₁₀)-alkyl,                —C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl,                —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,                —C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R₁ wherein R¹⁴ and y                are defined as in 7.7,            -   and wherein the R¹³ alkyl or phenyl groups in each case                are unsubstituted or mono- to penta-substituted by                substituents independently chosen from those as defined                under 1.7.1 to 1.7.11 above, or            -   R¹³ together with the nitrogen atom to which it is                bonded form a heterocycle having 5 to 7 ring atoms,        -   7.8 —O-phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11 above,        -   7.9 a radical selected from pyrrolidine, tetrahydropyridine,            piperidine, piperazine, imidazoline, pyrazolidine, furan,            morpholine, pyridine, pyridazine, pyrazine, oxolan,            imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine,            2-isothiazoline, thiophene or thiomorpholine,        -   7.10 —(C₃-C₇)-cycloalkyl or        -   7.11 ═O,    -   8. —N(R¹³)₂, wherein R¹³ is as defined in 1.7.7 above,    -   9. —NH—C(O)—R¹⁵, wherein R¹⁵ is        -   9.1 a radical selected from pyrrolidine, tetrahydropyridine,            piperidine, piperazine, imidazoline, pyrazolidine, furan,            morpholine, pyridine, pyridazine, pyrazine, oxolan,            imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine,            2-isothiazoline, thiophene or thiomorpholine, wherein said            radical is unsubstituted or mono- to penta-substituted by            substituents independently chosen from those as defined            under 1.7.1 to 1.7.11 above, —CF₃, benzyl or by            —(C₁-C₁₀)-alkyl, wherein alkyl is mono to tri-substituted by            substituents independently chosen from those as defined            under 1.7.1 to 1.7.11 above,        -   9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-            to penta-substituted by substituents independently chosen            from those as defined under 1.7.1 to 1.7.11 above or by            —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-            to penta-substituted by substituents independently chosen            from those as defined under 1.7.1 to 1.7.11 above,        -   9.3 —(C₃-C₇)-cycloalkyl,        -   9.4 —N(R¹³)₂₃ wherein R¹³ is as defined in 1.7.7 above, or        -   9.5 phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11 above, by            —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl,            wherein alkyl is mono to tri-substituted by substituents            independently chosen from those as defined under 1.7.1 to            1.7.11 above, or by two substituents of the phenyl radical            which form a dioxolan ring    -   10. —S(O)_(y)—R⁴, wherein R¹⁴ and y are as defined in 1.7.7        above,    -   11. —C(O)—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein        phenyl or alkyl are unsubstituted or mono- to penta-substituted        by substituents independently chosen from those as defined under        1.7.1 to 1.7.11 above,    -   12. —C(O)—O—R¹² ₃ wherein R¹² is as defined in 11. above,    -   13. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- to        penta-substituted by substituents independently chosen from        those as defined under 1.7.1 to 1.7.11 above,    -   14. —O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl,    -   15. —O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl or    -   16. —(C₁-C₄)-alkyl-N(R¹³)₂, wherein R¹³ is as defined in 1.7.7        above,-   R⁵ is as defined as R⁵ in case a) above,-   R⁶, R⁷ and R⁸ independently of one another are chosen from hydrogen    atom or methyl.    Examples include compounds of formula I, wherein in case a)-   B₆, B₇, B₈, and B₉ are each a carbon atom,-   R¹, R² and R³ independently of one another are chosen from hydrogen    atom, halogen, cyano, nitro, amino, —O—(C₁-C₇)-alkyl, wherein alkyl    is unsubstituted or substituted by phenyl, —CF₂—CF₃, —CF₃, —N(R¹⁸)₂,    -   wherein R¹⁸ is independently of one another chosen from hydrogen        atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl, —C(O)-pyridyl,        —C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or        —C(O)—(C₁-C₇)-alkyl, wherein alkyl, pyridyl or phenyl are        unsubstituted or mono- to tri-substituted by substituents        independently chosen from those as defined under 1.7.1 to        1.7.11, or R¹⁸ together with the nitrogen atom to which it is        bonded form a heterocycle having 5 to 7 ring atoms,-    S(O)_(y)—R¹⁴,    -   wherein y is zero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl,        which phenyl is unsubstituted or mono- to penta-substituted by        substituents independently chosen from those as defined under        1.7.1 to 1.7.11, amino or —N(R¹⁸)₂,    -   wherein R¹⁸ is as defined above,    -   wherein alkyl is unsubstituted or mono- to tri-substituted        independently of one another as defined under 1.7.1 to 1.7.11,        or-    —C(O)—O—R², wherein R¹² is as defined as in 1.11 above,-   R⁴ is cyano, amino, —O—(C₁-C₇)-alkyl, wherein alkyl is substituted    by phenyl;    -   —CF₂—CF₃, —CF₃, —N(R¹⁸)₂,        -   wherein R¹⁸ is independently of one another chosen from            hydrogen atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl,            —C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl,            —C(O)—O—(C₁-C₄)-alkyl or —C(O)—(C₁-C₇)-alkyl, wherein each            alkyl, pyridyl or phenyl are unsubstituted or mono- to            tri-substituted independently of one another as defined            under 1.7.1 to 1.7.11, or R¹⁸ together with the nitrogen            atom to which it is bonded form a heterocycle having 5 to 7            ring atoms,    -   S(O)_(y)—R¹⁴,        -   wherein y is zero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl,            phenyl, which phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11, amino or —N(R¹⁸)₂,        -   wherein R¹⁸ is as defined above,        -   wherein alkyl is unsubstituted or mono- to tri-substituted            by substituents independently chosen from those as defined            under 1.7.1 to 1.7.11, or    -   —C(O)—O—R², wherein R¹² is as defined above,-   R⁶, R⁷ and R⁸ independently of one another are chosen from hydrogen    atom or methyl, and-   R⁵ is as defined as for case a) above,-   or in case b)    -   the substituents R¹, R² and R⁴ independently of one another are        hydrogen atom, halogen, cyano, nitro, amino, —O—(C₁-C₇)-alkyl,        wherein alkyl is unsubstituted or substituted by phenyl,    -   —CF₂—CF₃, —CF₃, —N(R¹⁸)₂,        -   wherein R¹⁸ is independently of one another chosen from            hydrogen atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl,            —C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl,            —C(O)—O—(C₁-C₄)-alkyl or —C(O)—(C₁-C₇)-alkyl, wherein each            alkyl, pyridyl or phenyl are unsubstituted or mono- to            tri-substituted independently of one another as defined            under 1.7.1 to 1.7.11, or R¹⁸ together with the nitrogen            atom to which it is bonded form a heterocycle having 5 to 7            ring atoms,    -   S(O)_(y)—R¹⁴,        -   wherein y is zero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl,            phenyl, which phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 1.7.1 to 1.7.11, amino or —N(R¹⁸)₂,        -   wherein R¹⁸ is as defined above,        -   wherein alkyl is unsubstituted or mono- to tri-substituted            by substituents independently chosen from those as defined            under 1.7.1 to 1.7.11, or    -   —C(O)—O—R², wherein R¹² is as defined above,-   R³ is cyano, nitro, amino, —O—(C₁-C₇)-alkyl, wherein alkyl is    substituted by phenyl, —CF₂—CF₃, —CF₃, —N(R¹⁸)₂,    -   wherein R¹⁸ is independently of one another chosen from        hydrogen, atom,    -   —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl, —C(O)-pyridyl,        —C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or        —C(O)—(C₁-C₇)— alkyl, wherein each alkyl, pyridyl or phenyl are        unsubstituted or mono- to tri-substituted by substituents        independently chosen from those as defined under 1.7.1 to        1.7.11, or R¹⁸ together with the nitrogen atom to which it is        bonded form a heterocycle having 5 to 7 ring atoms,-    S(O)_(y)—R¹⁴,    -   wherein y is zero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl,        which phenyl is unsubstituted or mono- to penta-substituted by        substituents independently chosen from those as defined under        1.7.1 to 1.7.11, amino or —N(R¹⁸)₂,    -   wherein R¹⁸ is as defined above,    -   wherein alkyl is unsubstituted or mono- to tri-substituted        independently of one another as defined under 1.7.1 to 1.7.11,        or-    —C(O)—O—R², wherein R¹² is as defined above,-   R⁶, R⁷ and R⁸ independently of one another are chosen from hydrogen    atom or methyl, and-   R⁵ is as defined above.

Further examples include compounds of formula (II)

and/or a stereoisomeric form of the compound of the formula II and/or aphysiologically tolerable salt of the compound of the formula II,wherein;

-   R¹ and R² are independently of one another chosen from hydrogen    atom, halogen, cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃,    —CF₂—CF₃, —S(O)_(y)—R¹⁴,    -   wherein y is 1 or 2, R¹⁴ is amino, —(C₁-C₇)-alkyl or phenyl,        which phenyl is unsubstituted or mono- to tri-substituted as        defined for substituents under 1.7.1 to 1.7.11 above,    -   —N(R¹⁸)₂, wherein R¹⁸ is independently of one another chosen        from hydrogen atom, —(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl,        —C(O)-phenyl, C(O)-pyridyl, —C(O)—NH—(C₁-C₄)-alkyl,        —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or —(C₁-C₁₀)-alkyl,        wherein pyridyl, alkyl or phenyl are unsubstituted or mono- to        tri-substituted independently of one another as defined under        1.7.1 to 1.7.11, or        -   R¹⁸ together with nitrogen atom to which it is bonded form a            heterocycle having 5 to 7 ring atoms,-   R³ is cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃, —CF₂—CF₃,    —S(O)_(y)—R¹⁴, wherein y is 1 or 2, R¹⁴ is amino, —(C₁-C₇)-alkyl or    phenyl, which phenyl is unsubstituted or mono- to tri-substituted as    defined for substituents under 1.7.1 to 1.7.11 above,    -   —N(R¹⁸)₂, wherein R¹⁸ is independently of one another chosen        from hydrogen atom,    -   —(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl, —C(O)-pyridyl,        —C(O)—O-phenyl, —C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O—(C₁-C₄)-alkyl or        —(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl or phenyl are        unsubstituted or mono- to tri-substituted by substituents        independently chosen from those as defined under 1.7.1 to        1.7.11, or    -   R¹⁸ together with nitrogen atom to which it is bonded form a        heterocycle having 5 to 7 ring atoms, and-   R⁵ is hydrogen atom, —(C₁-C₁₀)-alkyl,    -   wherein alkyl is unsubstituted or mono- to tri-substituted by        substituents independently chosen from those as defined under        1.7.1 to 1.7.4,    -   —C(O)—R⁹ or —S(O)₂—R⁹, wherein        -   R⁹ is —(C₁-C₁₀)-alkyl, —O—(C₁-C₁₀)-alkyl,        -   wherein alkyl is unsubstituted or mono- to tri-substituted            independently of one another as defined under 1.7.1 to            1.7.4, or phenyl, which is unsubstituted or mono- to            tri-substituted as defined under 1.7.1 to 1.7.11, or            —N(R¹⁸)₂, wherein R¹⁸ is as defined above.

Still further examples are compounds of formula (II), wherein

-   R¹ is bromo, —CF₃ or chloro,-   R² is hydrogen atom or O—(C₁-C₂)-alkyl,-   R³ is —N(R¹⁸)₂, wherein R¹⁸ is independently of one another chosen    from hydrogen atom, —N—C(O)-pyridyl, —C(O)-phenyl, —(C₁-C₇)-alkyl,    —C(O)-(C₁-C₄)-alkyl or —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl or    phenyl are unsubstituted or mono- to tri-substituted by substituents    independently chosen from halogen or —O—(C₁-C₂)-alkyl, and-   R⁵ is hydrogen atom, methyl or —(O)₂—CH₃.

Specific compounds and all pharmaceutically acceptable salts thereofwhich are illustrative of the compounds of the invention include thefollowing;

Further specific examples include the following compounds:

N-(6-Chloro-9H-β-carbolin-8-yl)-nicotinamide, as well as the bismesylatesalt, bistrifluoracetate salt and bishydrochloride salt ofN-(6-Chloro-9H-β-carbolin-8-yl)-nicotinamide,N-(6-Chloro-9H-β-carbolin-8-yl)-3,4-difluoro-benzamide, as well as thehydrochloride salt ofN-(6-Chloro-9H-β-carbolin-8-yl)-3,4-difluoro-benzamide,N-(6-Chloro-7-methoxy-9H-β-carbolin-8-yl)-nicotinamide as well as thebistrifluoracetate salt and bishydrochloride salt ofN-(6-Chloro-7-methoxy-9H-β-carbolin-8-yl)-nicotinamide and6-Chloro-N-(6-chloro-9H-β-carbolin-8-yl)-nicotinamide.

The term “alkyl” by itself or as part on another substituent, unlessotherwise stated means a straight or branched chain hydrocarbon radicalhaving 1 to 10 carbon atoms such as methyl, ethyl, n-propyl, isopropyl,n-butyl, tertiary-butyl, pentyl, hexyl, heptyl, nonyl, octyl, decanyl orcycloalkyl having 3 to 7 carbon atoms such as cylopropyl, cyclobutyl,cyclohexyl or cycloheptyl.

The term “alkoxy” by itself or as part on another substituent, unlessotherwise stated means —O-alkyl or —O-substituted alkyl.

The term “heterocycle having 5 to 7 ring atoms” represents a radical ofa monocyclic saturated system having 5 to 7 ring members, which contains1, 2 or 3 heteroatoms as ring members. Examples of heteroatoms are N, Oand S. Examples of the term heterocycle having 5 to 7 ring atoms arepyrrolidine, tetrahydropyridine, piperidine, piperazine, imidazoline,pyrazolidine, furan, morpholine, pyridine, pyridazine, pyrazine, oxolan,imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine,2-isothiazoline, thiophene or thiomorpholine.

The term “aryl” by itself or as part on another substituent, unlessotherwise stated refers to an organic radical derived from an aromaticmolecule by removal of one atom; such as phenyl, pyridyl, thiazoly,morpholinyl and naphthyl.

The term “substituted alkyl” means an alkyl radical substituted at oneor more positions by one or more radicals of the group halogen, nitro,sulfo, amino, substituted amino, carboxyl, alkoxy, —O-aryl,—O-substituted aryl, and hydroxyl.

The term “substituted aryl” means an aryl radical substituted at one ormore positions by one or more radicals of the group halogen, alkyl,substituted alkyl, nitro, sulfo, amino, alkoxy, aryl, substituted aryl,or hydroxyl groups, such as an aryl radical substituted at 1 to 3positions by 1 to 3 groups.

The term “substituted amino” refers to —N(R¹³)₂ wherein R¹³ isindependently of one another chosen from hydrogen atom, sulfo, alkyl,aryl, —C(O)-alkyl, C(O)—NH-aryl, —C(O)—O-aryl, —C(O)—O-alkyl, orC(O)—O-aryl, wherein each alkyl or aryl may be independentlysubstituted.

The term “sulfo” refers to —S(O)_(y)—R⁴, wherein R¹⁴ is an alkyl, aryl,substituted aryl, substituted alkyl, amino, or substituted amino and yis zero, one or two.

The term “halogen” is understood as meaning fluorine, chlorine, bromineor iodine.

The term “—(C₁-C₄)-alkyl” is understood as meaning hydrocarbon radicalswhose carbon chain is linear or branched and contains 1 to 4 carbonatoms.

The invention further relates to a process for the preparation of thecompounds of formula I and/or stereoisomeric forms of the compounds ofthe formula I and/or physiologically tolerable salts of the compounds offormula I, which comprises

-   a) reacting a compound of formula III    -   in which R¹, R², R³, R⁴, B₆, B₇, B₈ and B₉ are each as defined        in formula I, with a compound of the formula IV,    -   in the presence of a acid, to yield a compound of the formula V-   which is reacted with hydrazine hydrate and later with formaldehyde    (R⁶ is H) or R⁶CHO to give a compound of formula VI    -   and oxidized to give a compound of the formula VI1,        where R¹ to R⁴, R⁶ to R⁸ and B₆ to B₉ are as defined in formula        I, a compound of formula (I), or-   b) a compound of the formula VII is reacted with a compound of the    formula VIII    Y—R⁵  (VIII)-    where Y is halogen or —OH and R⁵ is as defined in formula I, to    give a compound of the formula I, or-   c) resolving a compound of the formula I, which on account of its    chemical structure occurs in enantiomeric forms, prepared by    process a) or b) into the pure enantiomers by salt formation with    enantiomerically pure acids or bases, chromatography on chiral    stationary phases or derivatization by means of chiral    enantiomerically pure compounds such as amino acids, separation of    the diastereomers thus obtained, and removal of the chiral auxiliary    groups, or-   d) isolating the compound of the formula I prepared by process    a), b) or c) either in free form or, in the case of the presence of    acidic or basic groups, converting it into physiologically tolerable    salts.

The preparation of physiologically tolerable salts of compounds of theformula I capable of salt formation, including their stereoisomericforms, is carried out in a manner known per se. With basic reagents suchas hydroxides, carbonates, hydrogencarbonates, alkoxides and alsoammonia or organic bases, for example trimethyl- or triethylamine,ethanolamine or triethanolamine or alternatively basic amino acids, forexample lysine, ornithine or arginine, the carboxylic acids form stablealkali metal, alkaline earth metal or optionally substituted ammoniumsalts. If the compounds of the formula I contain basic groups, stableacid addition salts can also be prepared using strong acids. For this,both inorganic and organic acids such as hydrochloric, hydrobromic,sulfuric, phosphoric, methanesulfonic, benzenesulfonic,p-toluenesulfonic, 4-bromobenzenesulfonic, cyclohexylamidosulfonic,trifluoromethylsulfonic, acetic, oxalic, tartaric, succinic ortrifluoroacetic acid are suitable.

The invention also relates to pharmaceuticals which comprise anefficacious amount of at least one compound of the formula I and/or of aphysiologically tolerable salt of the compounds of the formula I and/oran optionally stereoisomeric form of the compounds of the formula I,together with a pharmaceutically suitable and physiologically tolerableexcipient, additive and/or other active compounds and auxiliaries.

On account of the pharmacological properties, the compounds according tothe invention are suitable for the prophylaxis and therapy of all thosedisorders in whose course an increased activity of IkB kinase isinvolved. These include, for example, asthma, rheumatoid arthritis (inthe case of inflammation), osteoarthritis, Alzheimer's disease,carcinomatous disorders (potentiation of cytotoxic therapies), cardiacinfarct or atherosclerosis.

The pharmaceuticals according to the invention are in generaladministered orally or parentally or by rectal, inhale or transdermaladministration.

The invention also relates to the use of the compounds of the formula I

and/or a stereoisomeric form of the compounds of the formula I and/or aphysiologically tolerable salt of the compounds of the formula I,for the production of pharmaceuticals for the prophylaxis and therapy ofdisorders in whose course an increased activity of IkB kinase isinvolved,wherein B₆, B₇, B₈ and B₉ are independently selected from the groupconsisting of carbon atom and nitrogen atom and wherein B₆, B₇, B₈ andB₉ together are no more than two nitrogen atoms at the same time;where the substituents R¹, R², R³, R⁴ and R⁸ may be independently chosenfrom

-   -   1. hydrogen atom,    -   2. halogen,    -   3. —OH,    -   4. —CN,    -   5. sulfo,    -   6. —NO₂,    -   7. —NH₂,    -   8. alkoxy,    -   9. substituted amino,    -   10. —NH—C(O)—R¹⁵, wherein R¹⁵ is a heterocycle having 5 to 7        ring atoms, an alkyl, an aryl, a substituted aryl or a        substituted alkyl,    -   11. —COOH,    -   12. —O—R¹⁰, wherein R¹⁰ is alkyl, substituted alkyl or aryl,    -   13. —C(O)—R¹², wherein R¹² is alkyl, substituted alkyl or aryl,    -   14. —C(O)—O—R², wherein R¹² is as defined in 13, above,    -   15. aryl,    -   16. —O-aryl,    -   17. substituted aryl,    -   18. —O-substituted aryl,    -   19. alkyl,    -   20. substituted alkyl,    -   21. —CF₃ or    -   22. —CF₂—CF₃,        provided that at least one of R¹, R², R³, R⁴ and R⁸ is not a        hydrogen atom,

-   R⁵ is 1. hydrogen atom,    -   2. alkyl,    -   3. alkyl radical, substituted at one or more positions by one or        more of the radicals, halogen, amino or hydroxyl,    -   4. —C(O)—R⁹ or    -   5. —S(O)₂—R⁹, in which        -   R⁹ is a) alkyl,            -   b) alkyl radical, substituted at one or more positions                by one or more of the radicals, halogen, amino or                hydroxyl,            -   c) aryl,            -   d) aryl radical, substituted at one or more positions by                one or more of the radicals, halogen, amino, or                hydroxyl,            -   e) —NH₂,            -   f) alkoxy or            -   g) substituted amino, and

-   R⁶ and R⁷ may be independently chosen from    -   1. hydrogen atom,    -   2. halogen,    -   3. —OH,    -   4. methyl,    -   5. —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- to        tri-substituted by substituents independently chosen from        -   5.1 aryl,        -   5.2 halogen,        -   5.3 —NO₂,        -   5.4 sulfo,        -   5.5 —COOH,        -   5.6 —NH₂,        -   5.7 —O—(C₁-C₄)-alkyl or        -   5.8 —OH, or    -   6. —N(R¹³)₂, wherein R¹³ is independently of one another chosen        from hydrogen atom, aryl, —C(O)—(C₁-C₄)-alkyl or substituted        aryl or alkyl, wherein said —C(O)—(C₁-C₄)— alkyl is        unsubstituted or mono- to tri-substituted independently of one        another as defined under 5.1 to 5.8, or        -   R¹³ together with the nitrogen atom to which it is bonded            form a heterocycle having 5 to 7 ring atoms.

Following are examples of the use of the compounds of formula I, wherein

-   B₆, B₇, B₈, and B₉ are each a carbon atom,-   R¹, R², R³, R⁴ and R⁸ are independently chosen from    -   1. hydrogen atom,    -   2. halogen,    -   3. —CN,    -   4. —COOH,    -   5. —NO₂,    -   6. —NH₂,    -   7. —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- to        penta-substituted by substituents independently chosen from 7.1        phenyl, which is unsubstituted or mono- to penta-substituted by        substituents independently chosen from halogen or        —O—(C₁-C₄)-alkyl,        -   7.2 halogen,        -   7.3 —NH₂,        -   7.4 —OH,        -   7.5 —COOR⁶, wherein R¹⁶ is hydogen atom or —(C₁-C₁₀)-alkyl,        -   7.6 —NO₂,        -   7.7 —S(O)—R¹⁴, wherein y is zero, 1 or 2, R¹⁴ is            —(C₁-C₁₀)-alkyl, phenyl, which phenyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 7.1 to 7.11, amino or            —N(R³)₂,            -   wherein R¹³ is independently of one another chosen from                hydrogen atom, phenyl, —(C₁-C₁₀)-alkyl,                —C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl,                —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,                —C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R¹⁴ wherein R¹⁴ and y                are as defined above,            -   and wherein R¹³ alkyl or phenyl groups in each case are                unsubstituted or mono- to penta-substituted by                substituents independently chosen from those as defined                under 7.1 to 7.11 above, or            -   R¹³ together with the nitrogen atom to which it is                bonded form a heterocycle having 5 to 7 ring atoms,        -   7.8 —O-phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 7.1 to 7.11 above,        -   7.9 a radical selected from pyrrolidine, tetrahydropyridine,            piperidine, piperazine, imidazoline, pyrazolidine, furan,            morpholine, pyridine, pyridazine, pyrazine, oxolan,            imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine,            2-isothiazoline, thiophene or thiomorpholine,        -   7.10 —(C₃-C₇)-cycloalkyl or        -   7.11 ═O,    -   8. —N(R³)₂, wherein R¹³ is as defined in 7.7 above,    -   9. —NH—C(O)—R₁ wherein R¹⁵ is        -   9.1 a radical selected from pyrrolidine, tetrahydropyridine,            piperidine, piperazine, imidazoline, pyrazolidine, furan,            morpholine, pyridine, pyridazine, pyrazine, oxolan,            imidazoline, isoxazolidine, 2-isoxazoline, isothiazolidine,            2-isothiazoline, thiophene or thiomorpholine,            -   wherein said radical is unsubstituted or mono- to                penta-substituted by substituents independently chosen                from those as defined under 7.1 to 7.11 above, —CF₃,                benzyl or by —(C₁-C₁₀)-alkyl, wherein alkyl is mono to                tri-substituted independently of one another as defined                under 7.1 to 7.11 above,        -   9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-            to penta-substituted by substituents independently chosen            from those as defined under 7.1 to 7.11 above or by            —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-            to penta-substituted by substituents independently chosen            from those as defined under 7.1 to 7.11 above,        -   9.3 —(C₃-C₇)-cycloalkyl,        -   9.4 —N(R¹³)₂, wherein R¹³ is as defined in 7.7 above, or        -   9.5 phenyl, wherein phenyl is unsubstituted or mono- to            penta-substituted by substituents independently chosen from            those as defined under 7.1 to 7.11 above, by            —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl,            wherein alkyl is mono to tri-substituted by substituents            independently chosen from those as defined under 7.1 to 7.11            above, or by two substituents of the phenyl radical which            form a dioxolan ring,    -   10. —S(O)_(y)—R¹⁴, wherein R¹⁴ and y are as defined in 7.7        above,    -   11. —C(O)—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein        phenyl or alkyl are unsubstituted or mono- to penta-substituted        by substituents independently chosen from those as defined under        7.1 to 7.11 above,    -   12. —C(O)—O—R², wherein R¹² is as defined in 11, above,    -   13. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- to        penta-substituted by substituents independently chosen from        those as defined under 7.1 to 7.11 above,    -   14. —O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl,    -   15. —O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl,    -   16. —(C₁-C₄)-alkyl-N(R¹³)₂, wherein R¹³ is as defined in 7.7        above    -   17. —CF₃ or    -   18. —CF₂—CF₃,        provided that at least one of R¹, R², R³, R⁴ and R⁸ is not a        hydrogen atom,-   R⁵ is 1. hydrogen atom,    -   2. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- to        penta-substituted by substituents independently chosen from        those as defined under 7.1 to 7.4 above,    -   3. —C(O)—R⁹, wherein R⁹ is        -   —NH₂, —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or            mono- to penta-substituted by substituents independently            chosen from those as defined under 7.1 to 7.4, or —N(R¹³)₂,            wherein R¹³ is as defined in 7.7 above, or    -   4. —S(O)₂—R⁹, wherein R⁹ is as defined in 3 above,-   or R⁴ and R⁵ together with the atom to which they are bonded form a    heterocycle,-   or R³ and R⁵ together with the atom to which they are bonded form a    heterocycle containing an additional oxygen atom in the ring and-   R⁶ and R⁷ independently of one another are chosen from hydrogen atom    or methyl.

Further examples include the use of compounds of formula I for theproduction of pharmaceuticals for the prophylaxis and therapy ofdisorders in whose course an increased activity of I_(k)B kinase isinvolved, wherein

-   B₆, B₇, B₈, and B₉ are each a carbon atom,-   R¹, R², R³ and R⁴ independently of one another are hydrogen atom,    halogen, cyano, nitro, amino, —O—(C₁-C₇)-alkyl, phenyl, —O-phenyl,    —CF₂—CF₃, —CF₃, N(R¹³)₂,    -   wherein R¹³ is independently of one another chosen from hydrogen        atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl, —C(O)-pyridyl,        —C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl,        —C(O)—(C₁-C₇)-alkyl or —(C₁-C₁₀)-alkyl, wherein alkyl, pyridyl        or phenyl are unsubstituted or mono- to tri-substituted by        substituents independently chosen from those as defined under        7.1 to 7.11, or R¹³ together with nitrogen atom to which it is        bonded form a heterocycle having 5 to 7 ring atoms,-    —S(O)_(y)—R¹⁴,    -   wherein y is zero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl,        which phenyl is unsubstituted or mono- to penta-substituted as        defined for substituents under 7.1 to 7.11, amino or —N(R¹³)₂,    -   wherein R¹³ is as defined above,    -   wherein alkyl is unsubstituted or mono- to tri-substituted        independently of one another as defined under 7.1 to 7.11, or-    —C(O)—O—R², wherein R¹² is as defined as in 11, above,-   R⁶, R⁷ and R⁸ independently of one another are hydrogen atom,    methyl, amino, —N(R¹³)₂, wherein R¹³ is as defined above,    provided that at least one of R¹, R², R³, R⁴ and R⁸ is not a    hydrogen atom, and R⁵ is as defined immediately above.

Moreover, examples include the use of compounds of formula II

and/or a stereoisomeric form of the compounds of the formula II and/or aphysiologically tolerable salt of the compounds of the formula II,for the production of pharmaceuticals for the prophylaxis and therapy ofdisorders in whose course an increased activity of I_(k)B kinase isinvolved, wherein;

-   R¹, R² and R³ are independently chosen from hydrogen atom, halogen,    cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃, —CF₂—CF₃, —S(O)_(y)—R⁴,    wherein y is 1 or 2,    -   R¹⁴ is amino, —(C₁-C₇)-alkyl, phenyl, which is unsubstituted or        mono- to tri-substituted by substituents independently chosen        from those as defined under 7.1 to 7.9, or —N(R¹³)₂, wherein    -   R¹³ is independently of one another chosen from —C(O)-pyridyl,        hydrogen atom, —(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl,        —(C₁-C₁₀)-alkyl, —C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O-phenyl or        —C(O)—O—(C₁-C₄)-alkyl, wherein        -   pyridyl, alkyl or phenyl are unsubstituted or mono- to            tri-substituted independently of one another as defined            under 7.1 to 7.11, or        -   R¹³ together with the nitrogen atom to which it is bonded            form a heterocycle having 5 to 7 ring atoms,            provided that at least one of R¹, R² and R³ is not a            hydrogen atom, and R⁵ is hydrogen atom, —(C₁-C₁₀)-alkyl,    -   wherein alkyl is unsubstituted or mono- to tri-substituted by        substituents independently chosen from those as defined under        7.1 to 7.4,    -   —C(O)—R⁹ or —S(O)₂—R⁹, wherein        -   R⁹ is —(C₁-C₁₀)-alkyl, —O—(C₁-C₁₀)-alkyl,        -   wherein alkyl is unsubstituted or mono- to tri-substituted            by substituents independently chosen from those as defined            under 7.1 to 7.4,        -   phenyl, which is unsubstituted or mono- to tri-substituted            by substituents independently chosen from those as defined            under 7.1 to 7.11, or —N(R¹³)₂,        -   wherein R¹³ is as defined directly above.

Still further examples include the use of the compounds of formula IIfor the production of pharmaceuticals for the prophylaxis and therapy ofdisorders in whose course an increased activity of I_(k)B kinase isinvolved, wherein

-   R¹, R² and R³ are independently chosen from hydrogen atom, halogen,    cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃ or N(R¹³)₂,    -   wherein R¹³ is independently of one another chosen from hydrogen        atom, —(C₁-C₇)-alkyl, —C(O)—(C₁-C₇)-alkyl, —C(O)-pyridyl,        —C(O)-phenyl or —C(O)—O—(C₀-C₄)-alkyl, wherein alkyl or phenyl        are unsubstituted or mono- to tri-substituted by substituents        independently chosen from halogen or —O—(C₁-C₄)-alkyl, and-   R⁵ is hydrogen atom, —C(O)—CH₃, methyl, —S(O)₂—CH₃,    —C(O)-morpholinyl, —CH₂—CH₂—OH or —CH₂—C(O)—NH₂,    provided that no more than two of R¹, R², R³ and R⁵ are a hydrogen    atom. Further examples include the use of the compounds of formula    II for the production of pharmaceuticals for the prophylaxis and    therapy of disorders in whose course an increased activity of IkB    kinase is involved, wherein-   R¹ is bromo, —CF₃ or chloro, R² is hydrogen atom or O—(C₁-C₂)-alkyl,-   R³ is hydrogen atom, bromo, chloro or —N(R¹³)₂,-   wherein R¹³ is independently of one another chosen from hydrogen    atom, —C(O)-phenyl, —(C₁-C₇)-alkyl, —C(O)—(C₁-C₄)-alkyl or    —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl or phenyl are unsubstituted or    mono- to tri-substituted by substituents independently chosen from    halogen or —O—(C₁-C₂)-alkyl, and-   R⁵ is hydrogen atom, —C(O)—CH₃, methyl or —S(O)₂—CH₃,    provided that no more than two of R¹, R², R³ and R⁵ are a hydrogen    atom.

Specific examples include the use of the compounds of formula II for theproduction of pharmaceuticals for the prophylaxis and therapy ofdisorders in whose course an increased activity of IkB kinase isinvolved, wherein

R¹ is chloro, R² and R³ are each hydrogen atom, and R⁵ is —C(O)—CH₃, or

R¹ is bromo, R² and R³ are each hydrogen atom, and R⁵ is —C(O)—CH₃, or

R¹ is chloro, R³ is —N—C(O)—CH₂—O—CH₃ and R² and R⁵ are each hydrogenatom, or

R¹ is chloro, R³ is —N—C(O)-para-fluoro-phenyl and R² and R⁵ are eachhydrogen atom, or R¹ and R³ are each chloro, R² is —C(O)—CH₃ and R⁵ ishydrogen atom, or

R¹ and R³ are each chloro, R⁵ is hydrogen atom and R² is —C(O)—CH₂—CH₃.

On account of the pharmacological properties, the compounds according tothe invention are suitable for the prophylaxis and therapy of all thosedisorders in whose course an increased activity of IkB kinase isinvolved. Disorders in whose course an increased activity of IkB kinaseis involved include, for example the treatment of joint inflammation,including arthritis, rheumatoid arthritis and other arthritic conditionssuch as rheumatoid spondylitis, gouty arthritis, traumatic arthritis,rubella arthritis, psoriatic arthritis and osteoarthritis. Additionally,the compounds are useful in the treatment of acute synovitis,tuberculosis, atherosclerosis, muscle degeneration, cachexia, Reiter'ssyndrome, endotoxaemia, sepsis, septic shock, endotoxic shock, gramnegative sepsis, gout, toxic shock syndrome, chronic pulmonaryinflammatory diseases including asthma and adult respiratory distresssyndrome, silicosis, pulmonary sarcoidosis, bone resorption diseases,reperfusion injury, carcinoses, leukemia, sarcomas, lymph node tumors,skin carcinoses, lymphoma, apoptosis, graft versus host reaction,allograft rejection and leprosy. Furthermore, the compounds are usefulin the treatment of: infections such as viral infections, for exampleHIV, cytomegalovirus (CMV), influenza, adenovirus and the Herpes groupof viruses, parasitic infections, for example malaria such as cerebralmalaria, and yeast and fungal infections, for example fungal meningitis;fever and myalgias due to infection; AIDS; AIDS related complex (ARC);cachexia secondary to infection or malignancy; cachexia secondary toacquired immune deficiency syndrome (AIDS) or to cancer; keloid and scartissue formation; pyresis; diabetes; and inflammatory bowel diseasessuch as Crohn's disease and ulcerative colitis. The compounds of theinvention are also useful in the treatment of diseases of or injury tothe brain in which over-expression of TNFα has been implicated such asmultiple sclerosis, and head trauma. The compounds according to theinvention are also useful in the treatment of psoriasis, Alzheimer'sdisease, carcinomatous disorders (potentiation of cytotoxic therapies),cardiac infarct, chronic obstructive pulmonary disease (COPD) and acuterespiratory distress syndrome (ARDS).

The invention also relates to a process for the production of apharmaceutical, which comprises bringing at least one compound of theformula I into a suitable administration form using a pharmaceuticallysuitable and physiologically tolerable excipient and, if appropriate,further suitable active compounds, additives or auxiliaries.

Suitable solid or pharmaceutical preparation forms are, for example,granules, powders, coated tablets, tablets, (micro)capsules,suppositories, syrups, juices, suspensions, emulsions, drops orinjectable solutions, and preparations having protracted release ofactive compound, in whose preparation customary auxiliaries, such asexcipients, disintegrants, binders, coating agents, swelling agents,glidants or lubricants, flavourings, sweeteners and solubilizers areused. Frequently used auxiliaries which may be mentioned are magnesiumcarbonate, titanium dioxide, lactose, mannitol and other sugars, talc,lactoprotein, gelatin, starch, cellulose and its derivatives, animal andvegetable oils such as cod liver oil, sunflower, groundnut or sesameoil, polyethylene glycol and solvents such as, for example, sterilewater and mono- or polyhydric alcohols such as glycerol.

The pharmaceutical preparations may be produced and administered in doseunits, each unit containing as active constituent a certain dose of thecompound of the formula I according to the invention. In the case ofsolid dose units such as tablets, capsules, coated tablets orsuppositories, this dose can be up to approximately 1000 mg, such asfrom approximately 50 mg to 300 mg and in the case of injectionsolutions in ampoule form up to approximately 300 mg, such as fromapproximately 10 mg to 100 mg.

For the treatment of an adult patient weighing approximately 70 kg,depending on the efficacy of the compound according to formula I, dailydoses of approximately 20 mg to 1000 mg of active compound, such as fromapproximately 100 mg to 500 mg, are indicated. Under certaincircumstances, however, even higher or lower daily doses may beappropriate. The administration of the daily dose can be carried outboth by single administration in the form of an individual dose unit orelse of a number of smaller dose units and by multiple administration ofsubdivided doses at specific intervals.

As a rule, final products are determined by mass-spectroscopic methods(FAB-, ESI-MS). Temperatures are given in degrees Celsius, RT means roomtemperature (22° C. to 26° C.). Abbreviations used are either explainedor correspond to the customary conventions.

The following examples are numbered so as to correspond to the compoundsof Table 1, below.

EXAMPLE 1 7-bromo-β-carboline

A solution of norharmane (600 mg, 3.57 mmol) in tetrahydrofuran (THF; 50ml) was treated with bromine (0.40 ml, 7.80 mmol) at RT while stirring.After stirring for 18 h at RT, the reaction was concentrated underreduced pressure and the resulting residue was sonicated in 10% aqueousNa₂CO₃ (100 ml). The product was filtered and washed with water to give905 mg of crude product. The crude product was crystallized from xylenesto provide in two crops 580 mg of 7-bromo-β-carboline.

EXAMPLE 2 1-acetyl-7-bromo-β-carboline

A solution of Example 1 (25 mg, 0.1 mmol) in dimetylformamide (DMF; 2ml) was treated with 0.10 ml of 1M aqueous NaOH (0.10 mmol). Afterstirring at RT for 30 minutes, acetic anhydride (0.010 ml, 0.095 mmol)was added and reaction stirred 18 h at RT. The reaction was partitionedin EtOAc and 5% citric acid and the organic layer washed with water,dried (brine; MgSO₄), and concentrated to give 23 mg of crude product.The crude product was chromatographed (7:3 hexane-acetone) on silica gelto give 10 mg of 1-acetyl-7-bromo-β-carboline.

EXAMPLE 3 7-fluoro-β-carboline

A mixture of 5-fluorotryptamine hydrochloride (200 mg, 0.93 mmol) inEtOAc (4 ml) and water (2 ml) was treated with glyoxalic acid hydrate(90 mg, 0.98 mmol). The pH of the aqueous layer was adjusted to 5 (with5% NaHCO₃ then 1M HCl) and the mixture stirred vigorously at RT for 18h. The mixture was then diluted with hexane (4 ml) and the productfiltered and washed with water and (1:1) hexane-ethyl acetate.

The crude product from above in 6N HCl (3 ml) was treated 3 times withconcentrated HCl (0.050 ml) every 15 min while refluxing. Afterrefluxing for a total of 45 min, the reaction was concentrated to give aresidue. The above residue was slurred in xylenes with triethylamine(0.40 ml, 2.9 mmol) and 10% Pd/C (200 mg). The mixture was refluxed for1 h and then filtered hot through celite. The filtrate was concentratedand the residue chromatographed (5:95 methanol-chloroform) on silica gelto give 25 mg of 7-fluoro-β-carboline.

EXAMPLE 4 7-isopropyl-β-carboline hydrochloride

A mixture of 4-isopropylphenylhydrazine hydrochloride (660 mg, 3.55mmol) and 4-phthalimidobutanal diethyl acetal (1.15 g, 3.95 mmol) inEthanol (EtOH; 30 ml) was heated at 60° C. to 65° C. for 1 h with water(0.050 ml). The mixture was then treated with concentrated HCl (0.50 ml)and refluxed for 14 h. After concentrating the reaction, the residue waspartioned in methylene chloride and saturated aqueous NaHCO₃. Theaqueous solution was extracted with methylene chloride (3 times) and thecombined organic solutions were dried (MgSO₄) and concentrated to giveafter chromatography (4:1 hexane-ethyl acetate) on silica gel 146 mg ofproduct.

The above product was treated with hydrazine hydrate (1 ml) in EtOH (4ml) and water (1 ml) and stirred at RT overnight. After concentratingthe reaction to an aqueous mixture, the product was extracted withmethylene chloride (3 times). The combined organic solution was dried(MgSO₄) and concentrated. The residue was redissolved in methylenechloride and treated with 1M HCl in ether. The precipitate was collectedand washed with ether and hexane and dried to provide 102 mg of6-isopropyltryptamine hydrochloride salt. This tryptamine obtained abovewas transformed into 7-Isopropyl-β-carboline according to the procedureused in example 3. The hydrochloride salt was obtained by treating asolution of 7-Isopropyl-β-carboline in methylene chloride with 1M HCl inether and concentrating. The residue was triturated with (1:1) methylenechloride-hexane to give 15 mg of 7-isopropyl-β-carboline hydrochloride.

EXAMPLE 5 7-cyano-β-carboline

A dark solution of example 1 (190 mg, 0.62 mmol) and CuCN (110 mg, 1.22mmol) in N-methyl 2-pyrrolidone (1.5 ml) was heated in a sealed reactiontube at 200° C. for 48 h. The mixture was filtered and the filtrate wasdiluted with water (50 ml). A brown solid that precipitated wasfiltered, washed with water, saturated aqueous NaHCO₃, and thenmethanol. This material was dissolved in DMSO and diluted with aqueousHCl. This homogeneous dark solution was decolorized with charcoal,filtered and concentrated to give a concentrated solution in DMSO. ThisDMSO solution was partitioned in (1:1) EtOAc-THF and saturated aqueousNaHCO₃. The organic solution was dried (MgSO₄) and concentrate to give 8mg of 7-cyano-β-carboline.

EXAMPLE 6 7-nitro-β-carboline hydrochloride

Norharmane (100 mg, 0.60 mmol) was treated with concentrated nitric acid(1.0 ml) and the resulting suspension was heated to 65° C. until themixture became homogeneous (3 to 4 min). The solution was carefullypoured into water (20 ml), and the precipitate filtered and washed withwater then methanol. The solid was suspended in saturated aqueous NaHCO₃and stirred vigorously before filtering and washing with water. Thesolid was taken up in hot methanol and this solution treated with 1M HClin ether (5 ml). The solution was concentrated and the residuetriturated with ether to provide

58 mg of a 7:3 mixture of 7-nitro-β-carboline hydrochloride and9-nitro-β-carboline hydrochloride.

EXAMPLE 7 7-carboxy-β-carboline trifluoroacetat

Crude product from example 5 (from 210 mg of example 1, 0.85 mmol) wastreated with 6 M HCl in a sealed reaction tube for 15 h at 110° C. Thereaction was evaporated to give a concentrated solution of product inN-methyl 2-pyrrolidone. A portion (half) was purified by preparativeHPLC using a C₁₈-packed column and eluting with a gradient (5:95 to50:50) of water-acetonitril (with 0.1% trifluoracetic acid). The purefractions were combined and lyophilized to provide 11 mg of7-carboxy-β-carboline trifluoroacetate.

EXAMPLE 8 7,9-dibromo-β-carboline hydrochloride

A solution of the product from example 1 (140 mg, 0.58 mmol) in THF (2ml) was treated with bromine (0.50 ml). After 10 min at RT, the reactionwas diluted with chloroform and the product was filtered. The filteredproduct was taken up in methanol and treated with 1M HCl in ether andconcentrated. The residue was triturated with ether to provide 160 mg of7,9-dibromo-β-carboline hydrochloride.

EXAMPLE 9 7,9-dichloro-β-carboline

To a suspension of norharmane (84 mg, 0.50 mmol) in water (3 ml) at RTwas added 1M aqueous HCl (1.1 ml, 1.1 mmol). To this homogenous solutionwas added N-chlorosuccinimide (747 mg, 5.58 mmol) portionwise and theresulting solution was stirred at 60° C. to 70° C. for 3 h. The reactionwas partitioned in EtOAc and saturated aqueous NaHCO₃ and the organiclayer was dried (brine; MgSO₄) and then concentrated. The residue waschromatographed (2:3 THF-hexane) on silica gel to give 24 mg of7,9-dichloro-β-carboline after triturating with (1:1) methylenechloride-hexane, then with hexane.

EXAMPLE 10 1-acetyl-7-bromo-β-carboline

To a suspension of NaH (95%, 14 mg, 0.60 mmol) in DMF (1.0 ml) at 5° C.to 10° C. was added the product from example 1 (74 mg, 0.30 mmol). Theresulting mixture was stirred for 15 min at 5° C. to 10° C. beforeadding methanesulfonylchloride (0.030 ml, 0.38 mmol). The reaction wasallowed to warm to RT and stirred for 2 h before partitioning intosaturated aqueous NaHCO₃ and EtOAc. After stirring the mixtureovernight, the organic layer was washed with water, dried (brine;MgSO₄), and concentrated. The residue was purified by chromatography(1:1 hexane-ethyl acetate) on silica gel to give 23 mg of1-acetyl-7-bromo-β-carboline.

EXAMPLE 11 7-bromo-1-methyl-β-carboline

To a suspension of NaH (95%, 6 mg, 0.24 mmol) in DMF (2.0 ml) at 5° C.to 10° C. was added the product from example 1 (50 mg, 0.20 mmol). Theresulting mixture was stirred for 15 min at 5° C. to 10° C. beforeadding methyl-iodide (0.030 ml, 0.20 mmol) at 0° C. to 5° C. Thereaction was stirred for 12 h at 0° C. to 5° C. before partitioning intowater and EtOAc. The organic layer was washed with water, dried (brine;MgSO₄), and concentrated. The residue was purified by chromatography(gradient, 1:3 hexane-ethyl acetate to ethyl acetate) on silica gel togive 10 mg of 7-bromo-1-metyhl-β-carboline.

EXAMPLE 12 7-chloro-β-carboline

To a solution of norharmane (2.0 g, 11.9 mmol) in water (89 ml) and 1Maqueous HCl (29.8 ml, 29.8 mmol) was added N-chlorosuccinimide (3.17 g,23.8 mmol) portionwise. The resulting solution was stirred at RT for 6h, and then at 0° C. to 5° C. for 12 h. The reaction was diluted withwater (100 ml) and basified cautiously with solid K₂CO₃ (4.3 g). Afterstirring at RT for 1 h, the product was collected and washed with water.The crude product was refluxed in chloroform for 1 h and filtered aftercooling to 15° C. to provide 2.05 g of 7-chloro-β-carboline.

EXAMPLE 13 1-acetyl-7-chloro-β-carboline

To a solution of the product from example 12 (104 mg, 0.50 mmol) in DMF(2.0 ml) at 3° C. to 5° C. was added NaH (95%, 15 mg, 0.625 mmol). Theresulting mixture was stirred for 15 min before adding acetic anhydride(0.083 ml, 0.875 mmol). The reaction was allowed to warm to RT andstirred for 3 h before pouring into with water (25 ml). The slurry wasstirred for 12 h, and the product collected to give after chromatography(1:3 hexane-ethyl acetate) on silica gel 82 mg of1-acetyl-7-chloro-β-carboline.

EXAMPLE 14 7-chloro-9-nitro-β-carboline

A mixture of the product from example 12 (500 mg, 2.48 mmol) inconcentrated nitric acid (20 ml) was stirred at RT for 22 h. Thereaction mixture was carefully poured into cold (3° C. to 5° C.) water(50 ml), and after stirring for 2 h the precipitate was collected. Thesolid was suspended in saturated aqueous NaHCO₃ (50 ml) and stirred atRT for 12 h. The product was filtered and washed with water to provide550 mg of 7-chloro-9-nitro-β-carboline

EXAMPLE 15 9-amino-7-chloro-β-carboline

To a suspension of the product from example 14 (548 mg, 2.22 mmol) inEtOH (14 ml) at 65° C. to 70° C. was added tin chloride dihydrate (2.5g, 11.1 mmol). Thereafter, 6M aqueous HCl (14 ml) was added dropwise.The mixture was stirred at 70° C. to 80° C. for 3.5 h and thenpartitioned slowly into saturated aqueous NaHCO₃ (150 ml) and EtOAc (100ml). The aqueous phase was extracted (2 times) and the combined organicsolutions dried (brine; NaSO₄) and concentrated to give 484 mg of9-amino-7-chloro-β-carboline.

EXAMPLE 16 9-amino-7-chloro-β-carboline trifuoroacetate

To a solution of the product from example 15 (35 mg, 0.16 mmol) inpyridine (0.80 ml) was added acetic anhydride (0.018 ml, 0.19 mmol). Theresulting mixture was allowed to stand at RT for 12 h before pouringinto water (15 ml). The crude product was filtered and purified bypreparative HPLC using a C₁₈-packed column and eluting with a gradient(5:95 to 60:40) of water-acetonitril (with 0.1% trifluoracetic acid).The pure fractions were combined and lyophilized to provide 18 mg of9-amino-7-chloro-β-carboline trifluoroacetate.

EXAMPLE 17 7-bromo-1-carbonyl-(4′-morpholine)-β-carboline

A solution of the product from example 1 (125 mg, 0.51 mmol) in DMF (2ml) was treated with 0.55 ml of 1M aqueous NaOH (0.55 mmol). Afterstirring at RT for 30 minutes, 4-morpholinecarbonyl chloride (0.060 ml,0.51 mmol) was added and reaction stirred 18 h at RT. The reaction waspartitioned in EtOAc and 5% citric acid and the organic layer washedwith water, dried (brine; MgSO₄), and concentrated. The residue waschromatographed (7:3 hexane-acetone) on silica gel to give 105 mg of7-bromo-1-carbonyl-(4′-morpholino)-β-carboline.

EXAMPLE 18 1-(2′-ethylacetate)-7-chloro-β-carboline

To a suspension of NaH (95%, 28 mg, 1.15 mmol) in DMF (1.0 ml) at 5° C.to 10° C. was added the product from example 12 (202 mg, 1.0 mmol) inDMF (3 ml). The resulting mixture was stirred for 30 min at 5° C. to 10°C. before adding ethyl bromoacetate (0.116 ml, 1.05 mmol). The reactionwas allowed to be stirred for 1.5 h and then the reaction was dilutedwith saturated aqueous NaHCO₃ (30 ml). The product was extracted withEtOAc (30 ml; 2 times each 15 ml), and the combined organic extractswere dried (brine; MgSO₄) then concentrated. The residue was purified bychromatography (1:3 hexane-ethyl acetate) on silica gel to give 270 mgof 1-(2′-ethylacetate)-7-chloro-β-carboline.

EXAMPLE 19 1-(2′-ethanoyl)-7-chloro-β-carboline

To a solution of the product from example 18 (50 mg, 0.17 mmol) in THF(1.7 ml) at 5° C. to 10° C. was added 1M LAH in THF (0.17 ml, 0.17mmol). The resulting mixture was stirred for 2 h at 5° C. to 10° C.before adding EtOAc (0.10 ml). The mixture was subsequently diluted withEtOAc (5 ml) and slowly treated with saturated aqueous NaHCO3 (5 ml).After diluting with water (10 ml) and brine (10 ml) the mixture wasextracted with EtOAc. The organic solution was dried (brine; MgSO₄) thenconcentrated to give 42 mg of 1-(2′ethanol)-7-chloro-β-carboline.

EXAMPLE 20 1-(2′-acetyl)-7-chloro-β-carboline

To a solution of the product from example 18 (107 mg, 0.37 mmol) in MeOH(3.7 ml) at RT was added water (3.7 ml) followed by treatment with 1Maqueous NaOH (0.41 ml, 0.41 mmol). The resulting mixture was stirred for2 h and the volatile removed under reduced pressure. The mixture wassubsequently diluted with water (5 ml) and the pH adjusted to 5 to 6.The precipitate was filtered and washed with water to give 96 mg of1-(2′-acetyl)-7-chloro-β-carboline.

EXAMPLE 21 8-methoxy-β-carboline

Prepared from 6-methoxytryptamine using the procedure as in example 3.

EXAMPLE 22 See Table 1 for Structure

To a solution of the product from example 20 (59 mg, 0.23 mmol) in DMF(2.8 ml) at RT was added p-nitrophenol (40 mg, 0.29 mmol) followed by1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (48 mg, 0.25 mmol). Theresulting mixture was stirred for 1.5 h at RT and then ammoniumbicarbonate (55 mg, 0.69 mmol) was added. The reaction was stirred for18 h at RT and then poured into water (20 ml). The aqueous mixture wasbasified to pH of about 10 with K₂CO₃. The precipitate was filtered andwashed with water to give 47 mg of the title compound.

EXAMPLE 23 8-hydroxy-2-methyl-β-carboline

A solution of harmine (616 mg, 2.9 mmol) in dichloroethane (20 ml) wastreated with 2.0 ml of 1M BBr₃ (4 mmol) in dichloroethane. The reactionwas stirred at 60° C. for 48 h and then cooled to 0° C. before quenchingwith MeOH (5 ml). The reaction was concentrated and the residuetriturated with methanol to give 413 mg of8-hydroxy-2-methyl-β-carboline.

EXAMPLE 24 6,8-dibromo-7-methoxy-β-carboline

A solution of the product from example 30 (90 mg, 0.45 mmol) in aceticacid (8 ml) was treated with bromine (0.025 ml, 0.48 mmol). The reactionwas stirred at RT for 18 h and then concentrated. The residue waspartitioned in EtOAc and aqueous NaHCO₃. The organic layer was dried(brine; MgSO₄) and concentrated. The residue was purified bychromatography. (5:4 hexane-acetone) on silica gel to give 3 mg of6,8-dibromo-7-methoxy-β-carboline.

EXAMPLE 25 See Table 1 for Structure

A solution of the product from example 23 (60 mg, 0.30 mmol) in DMF (3ml) was treated with K₂CO₃ (100 mg) and t-butyl bromoacetate (0,040 ml,0.27 mmol). After stirring at RT for 18 h, the reaction was partitionedin EtOAc and water. The organic layer was dried (brine; MgSO₄) and thenconcentrated. The residue was chromatographed (1:1 hexane-EtOAc) onsilica gel to give 20 mg of the title compound.

EXAMPLE 26 See Table for Structure

A solution of the product from example 23 (50 mg, 0.25 mmol) in DMF (3ml) was treated with K₂CO₃ (100 mg) and benzyl bromide (0,030 ml, 0.25mmol). After stirring at RT for 18 h, the reaction was partitioned inEtOAc and water. The organic layer was dried (brine; MgSO₄) and thenconcentrated. The residue was chromatographed (1:1 hexane-EtOAc) onsilica gel to give 12 mg of the title compound.

EXAMPLE 27 7-ethoxy-2-methyl-β-carboline

A solution of the product from example 23 (60 mg, 0.30 mmol) in DMF (3ml) was treated with K₂CO₃ (100 mg) and ethyl iodide (0,029 ml, 0.36mmol). After stirring at RT for 18 h, the reaction was partitioned inEtOAc and water. The organic layer was dried (brine; MgSO₄) and thenconcentrated. The residue was chromatographed (1:1 hexane-acetone) onsilica gel to give 20 mg of 7-ethoxy-2-methyl-β-carboline.

EXAMPLE 28 7-bromo-2-methyl-β-carboline

Prepared from harmane using the same procedure as in example 1.

EXAMPLE 29 See Table 1 for Structure

A solution of the product from example 23 (60 mg, 0.30 mmol) in DMF (3ml) was treated with K₂CO₃ (100 mg) and acetic anhydride (0,034 ml, 0.36mmol). After stirring at RT for 18 h, the reaction was partitioned inEtOAc and water. The organic layer was dried (brine; MgSO₄) and thenconcentrated. The residue was chromatographed (1:1 hexane-acetone) onsilica gel to give 18 mg of the title compound.

EXAMPLE 30 7-methoxy-β-carboline

Prepared from 5-methoxytryptamine using the procedure in example 3.

EXAMPLE 31 8-fluoro-β-carboline

Prepared from 6-fluorotryptamine using the same procedure as in example3.

EXAMPLE 32 7-bromo-2-methyl-8-methoxy-β-carboline

Prepared from harmine using the same procedure as in example 1.

EXAMPLE 33 7-hydroxy-β-carboline

Prepared from the product of example 30 using the procedure in example23.

EXAMPLE 34 7-chloro-8-fluoro-β-carboline

Prepared from the product of example 31 using the procedure in example12.

EXAMPLE 35 7-methoxy-1-methyl-β-carboline

Prepared from the product of example 30 using the procedure in example11.

EXAMPLE 36 9-chloro-8-methoxy-β-carboline trifluoroacetate EXAMPLE 377,9-dichloro-8-methoxy-β-carboline trifluoroacetate

A solution of the product from example 21 (195 mg, 1.0 mmol) in 1M HCl(3 ml) was treated with N-chlorosuccinimide (270 mg, 2 mmol) portionwiseand the resulting solution was stirred at 60° C. to 70° C. for 3 h. Thereaction was evaporated and the crude product purified by preparativeHPLC using a C₁₈-packed column and eluting with a gradient (5:95 to50:50) of water-acetonitril (with 0.1% trifluoroacetic acid). The purefractions of each product were combined and lyophilized to provide 78 mgof 9-chloro-8-methoxy-β-carboline trifluoroacetate and 51 mg of7,9-dichloro-8-methoxy-β-carboline trifluoroacetate.

EXAMPLE 38 7,9-dichloro-8-hydroxy-β-carboline

A mixture of the product of example 37 (590 mg, 2.21 mmol) in methylenechloride (25 ml) at 35° C. was treated with a solution of BBr₃ inmethylene chloride (1M, 6 ml, 6 mmol). After refluxing for 3 h, thereaction was quenched with methanol (5 ml) and then concentrated. Theresidue was slurred in 60% NaHCO₃ solution, the product filtered andwashed with water to give 500 mg of 7,9-dichloro-8-hydroxy-β-carboline.

EXAMPLE 39 7,9-dichloro-8-ethoxy-β-carboline

A mixture of the product of example 38 (35 mg, 0.14 mmol), K₂CO₃ (100mg), and ethyl iodide (0.014 ml, 0.17 mmol) in acetone (5 ml) wasstirred in a closed reaction tube at RT for 3 days. After concentratingthe reaction, the residue was partitioned in ethyl acetate and water.The organic layer was dried (MgSO4) and concentrated to give crudeproduct. The crude product was chromatographed (5% methanol inchloroform) on silica gel to give 8 mg of7,9-dichloro-8-ethoxy-β-carboline.

EXAMPLE 40 7-chloro-8-fluoro-β-carboline trifluoroacetate

A solution of the product of example 31 (78 mg, 0.42 mmol) in 1M HCl (1ml) was treated with N-chlorosuccinimide (115 mg, 0.9 mmol) portionwiseand the resulting mixture was stirred at 60° C. to 70° C. for 3 h. Thereaction was evaporated and the crude product purified by preparativeHPLC using a C₁₈-packed column and eluting with a gradient (5:95 to50:50) of water-acetonitril (with 0.1% trifluoroacetic acid). The purefractions with product were combined and lyophilized to provide 33 mg ofthe title compound.

EXAMPLE 41 1-hydroxy-7-trifluoromethyl-β-carboline EXAMPLE 427-trifluoromethyl-β-carboline

A solution of 3-hydroxy-2-piperdone (96 mg, 0.83 mmol) in methylenechloride (5 ml) was treated with Dess Martin reagent (352 mg, 0.85 mmol)at RT and the resulting mixture was stirred for 1 h. After filtering thesalts from the reaction, the ketone in solution was treated with4-trifluoromethyl-phenylhydrazine (145 mg, 0.83 mmol). After 15 min,hexane (20 ml) was added and the hydrazone collected by filtration. Thiscrude hydrazone was heated at 95° C. in formic acid (70%, 10 ml) for 1h. The reaction was evaporated and the residue was chromatographed(ethyl acetate) on silica gel to give 60 mg of dihydro1-hydroxy-7-trifluoromethyl-β-carboline.

A portion of dihydro 1-hydroxy-7-trifluoromethyl-β-carboline (6 mg) inxylenes (1 ml) was treated with Pd/C (10%, 7 mg) and the mixture heatedat 50° C. for one week. The reaction was concentrated after filtering itthrough celite, and the residue was chromatographed (1:1 hexane-ethylacetate) on silica gel to give 1 mg of1-hydroxy-7-trifluoromethyl-β-carboline.

A portion of dihydro 1-hydroxy-7-trifluoromethyl-β-carboline (25 mg) inTHF (1 ml) was treated with a solution of lithium aluminum hydride inTHF (1M, 0.5 ml). The reaction was stirred at 60° C. for 6 h beforequenching with water (5 ml) and extracting with ethyl acetate (3 times10 ml). The combined organic layers were dried (MgSO₄) and concentratedto provide tetrahydro 7-trifluoro-methyl-β-carboline. This material wastaken up in xylenes (5 ml) and treated with Pd/C (10%, 15 mg). Themixture was stirred at 150° C. for 48 h before filtering through celiteand concentrating. The residue was chromatographed (ethyl acetate) onsilica gel to give 5 mg of 7-tri-fluoromethyl-β-carboline.

EXAMPLE 43 7-chloro-9-(methylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (50 mg, 0.23 mmol) inAcOH/methanol (1%, 3 ml) was treated with sodium cyanoborohydride (30mg, 0.46 mmol) followed by formaldehyde (37%, 0.017 ml, 0.23 mmol). Thereaction was stirred at RT for 36 h and then diluted with saturatedNaHCO₃ (9 ml). After stirring for 15 min, the crude product was filteredand washed with water. The crude product was purified as described inexample 46. The pure fractions with product were combined andlyophilized to provide 13 mg of the title compound.

EXAMPLE 44 7-chloro-9-(dimethylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (50 mg, 0.23 mmol) inAcOH/methanol (1%, 3 ml) was treated with sodium cyanoborohydride (30mg, 0.46 mmol) followed by formaldehyde (37%, 0.060 ml, 0.69 mmol). Thereaction was stirred at RT for 36 h and then diluted with saturatedNaHCO₃ (9 ml). After stirring for 15 min, the crude product was filteredand washed with water. The crude product was purified as described inexample 46. The pure fractions with product were combined andlyophilized to provide 40 mg of the title compound.

EXAMPLE 45 7-chloro-9-(methylsulfonylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(0.5 ml) was treated with methanesulfonyl chloride (0.024 ml, 0.30 mmol)in two portions over 30 h. The reaction was diluted with water (5 ml)and the crude product collected and washed with water (several times).The crude product was purified as described in example 46. The purefractions with product were combined and lyophilized to provide 16 mg ofthe title compound.

EXAMPLE 46 7-chloro-9-(propylonylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(1.0 ml) was treated with propionyl chloride (0.015 ml, 0.17 mmol).After stirring at RT for 4 h, the reaction was diluted with water (9 ml)and saturated NaHCO₃ (1 ml). The crude product was collected and washedwith water (several times). The crude product was purified bypreparative HPLC using a C₁₈-packed column and eluting with a gradient(5:95 to 50:50) of water-acetonitril (with 0.1% trifluoroacetic acid).The pure fractions with product were combined and lyophilized to provide21 mg of the title compound.

EXAMPLE 47 7-chloro-9-(benzoylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(1.0 ml) was treated with benzoyl chloride (0.020 ml, 0.17 mmol). Afterstirring at RT for 4 h, the reaction was diluted with water (9 ml) andsaturated NaHCO₃ (1 ml). The crude product was collected and washed withwater (several times). The crude product was purified as described inexample 46. The pure fractions with product were combined andlyophilized to provide 12 mg of 7-chloro-9-(benzoylamino)-β-carbolinetrifluoroacetate.

EXAMPLE 48 7-chloro-9-(Acetyl-methylamino)-β-carboline trifluoroacetate

A solution of the product of example 43 (19 mg, 0.082 mmol) in pyridine(0.40 ml) was treated with acetic anhydride (0.037 ml, 0.36 mmol) in twoportions over 48 h. The reaction was subsequently concentrated todryness and the residue coevaporated with AcOH under reduced pressure.The crude product was purified as described in example 46. The purefractions with product were combined and lyophilized to provide 9 mg ofthe title compound.

EXAMPLE 49 7-chloro-9-(4-fluorobenzoylamino)-β-carbolinetrifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(1.0 ml) was treated with 4-fluorobenzoyl chloride (0.018 ml, 0.17mmol). After stirring at RT for 18 h, the reaction was diluted withwater (10 ml). The crude product was purified as described in example46. The pure fractions with product were combined and lyophilized toprovide 13 mg of the title compound.

EXAMPLE 50

A cold (3° C. to 5° C.) solution of the product of example 15 (30 mg,0.14 mmol) and pyridine (0.014 ml, 0.17 mmol) in THF (0.7 ml) wastreated with phenyl chloroformate (0.018 ml, 0.145 mmol). After stirringat RT for 2 h, the reaction was partitioned in ethyl acetate and buffer(pH 7.2). The organic layer was dried (brine, Na2SO₄) and concentratedto give 43 mg of phenyl carbamate.

To a solution of phenyl carbamate (30 mg, 0.089 mmol) in DMSO (0.5 ml)was added 2-methoxyethylamine (0.010 ml, 0.10 mmol). After stirring atRT for 30 min, the crude reaction mixture was purified as described inexample 46. The pure fractions with product were combined andlyophilized to provide 21 mg of the title compound.

EXAMPLE 51 7-chloro-9-(methoxyacetylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (35 mg, 0.16 mmol) in pyridine(1.0 ml) was treated with methoxyacetyl chloride (0.016 ml, 0.18 mmol).After stirring at RT for 2 h, the reaction was diluted with water (10ml). The crude product was purified as described in example 46. The purefractions with product were combined and lyophilized to provide 32 mg ofthe title compound.

EXAMPLE 52 7-chloro-9-(3-methoxybenzoxylamino)-β-carbolinetrifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(1.0 ml) was treated with m-anisoyl chloride (0.027 ml, 0.19 mmol) intwo portions over 6 h. The reaction was subsequently diluted with water(10 ml) and the crude product was purified as described in example 46.The pure fractions with product were combined and lyophilized to provide33 mg of the title compound.

EXAMPLE 53 7-chloro-9-(4-methoxybenzoxylamino)-β-carbolinetrifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(1.0 ml) was treated with p-anisoyl chloride (37 mg, 0.22 mmol) in twoportions over 24 h. The reaction was subsequently diluted with water (10ml) and the crude product was purified as described in example 46. Thepure fractions with product were combined and lyophilized to provide 24mg of the title compound.

EXAMPLE 54 7-chloro-9-(methylcarbamylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (30 mg, 0.14 mmol) in pyridine(1.0 ml) was treated with p-anisoyl chloride (0.017 ml, 0.21 mmol) intwo portions over 4 h. The reaction was subsequently diluted with water(10 ml) and the crude product was purified as described in example 46.The pure fractions with product were combined and lyophilized to provide35 mg of the title compound.

EXAMPLE 55 7-chloro-9-(isovalerylamino)-β-carboline trifluoroacetate

A solution of the product of example 15 (35 mg, 0.16 mmol) in pyridine(1.0 ml) was treated with isovalerylchloride (0.033 ml, 0.28 mmol) intwo portions over 24 h. The reaction was subsequently diluted with water(10 ml) and the crude product was purified as described in example 46.The pure fractions with product were combined and lyophilized to provide52 mg of the title compound.

EXAMPLE 60 N-(6-Chloro-9H-β-carbolin-8-yl)-nicotinamide

To a solution of norharmane (2.0 g, 11.9 mmol) in water (89 ml) and 1Maqueous HCl (29.8 ml, 29.8 mmol) was added N-chlorosuccinimide (3.17 g,23.8 mmol) portionwise. The resulting solution was stirred at RT for 6h, and then at 0° C. to 5° C. for 12 h. The reaction was diluted withwater (100 ml) and basified cautiously with solid K₂CO₃ (4.3 g). Afterstirring at RT for 1 h, the product was collected and washed with water.The crude product was refluxed in chloroform for 1 h and filtered aftercooling to 15° C. to provide 2.05 g of 7-chloro-β-carboline.

A mixture 7-chloro-β-carboline (500 mg, 2.48 mmol) in concentratednitric acid (20 ml) was stirred at RT for 22 h. The reaction mixture wascarefully poured into cold (3° C. to 5° C.) water (50 ml), and afterstirring for 2 h the precipitate was collected. The solid was suspendedin saturated aqueous NaHCO₃ (50 ml) and stirred at RT for 12 h. Theproduct was filtered and washed with water to provide 550 mg of7-chloro-9-nitro-β-carboline.

To a suspension of 7-chloro-9-nitro-β-carboline (548 mg, 2.22 mmol) inEtOH (14 ml) at 65° C. to 70° C. was added tin chloride dihydrate (2.5g, 11.1 mmol). Thereafter, 6M aqueous HCl (14 ml) was added dropwise.The mixture was stirred at 70° C. to 80° C. for 3.5 h and thenpartitioned slowly into saturated aqueous NaHCO₃ (150 ml) and EtOAc (100ml). The aqueous phase was extracted (2 times) and the combined organicsolutions dried (brine; NaSO₄) and concentrated to give 484 mg of9-amino-7-chloro-β-carboline.

To a cold (3-5° C.) solution of 9-amino-7-chloro-β-carboline (2.75 g,12.7 mmol) in pyridine (150 ml) was added nicotinyl chloridehydrochloride (2.82 g, 15.8 mmol). The reaction was allowed to warm toRT and stirred for 20 h before diluting the reaction with water (100 ml)and 1M NaOH (25 ml). After stirring for 1 h at RT, the mixture waspoured into water (200 ml). The mixture was allowed to stand for 1 h andthe product was filtered to provide 3.80 g of the title compound afterwashing with water and drying under reduced pressure at RT.

EXAMPLE 68 N-(6-Chloro-7-methoxy-9H-β-carbolin-8-yl)-nicotinamide

A mixture of 6-methoxytryptamine (9.10 g, 47.8 mmol) in EtOAc (40 ml)and pH 4.5 NaOAc buffer (40 ml) was treated with glyoxalic acid hydrate(5.30, 57.6 mmol). The mixture was stirred vigorously for 2 days andthen diluted with hexane (40 ml). The product was filtered and washedwith water and (1:1) hexane-ethyl acetate. The crude product wascrystallized from methanol after filtration of a hot methanol solution.

The crude product (11.5 g) from above in 6N HCl (100 ml) was treated 3times with concentrated HCl (5.0 ml) every 15 min while refluxing. Afterrefluxing for a total of 1 h, the reaction was concentrated to give aresidue. This residue was slurried and sionicated with 10% Na₂CO₃ (300ml) and filtered to give the free amine (7.20 g). The above amine wasrefluxed in xylenes (200 ml) and pyridine (100 ml) with 10% Pd/C (3 g)for 5 h. The hot reaction was filtered thru celite and the filtrate wasconcentrated to give 6.38 g of 8-methoxy-β-carboline.

To a mixture of 8-methoxy-β-carboline (1.0 g, 5 mmol) in THF (100 ml)was added N-chlorosuccinimide (0.70 g, 5.2 mmol). The reaction wasstirred at RT for 4 h before concentrating and washing the residue with1:1:1 mixture of 10% Na₂CO₃, hexane, and EtOAc (400 ml). The resultingresidue was triturated with xylenes to provide 677 mg of7-chloro-8-methoxy-β-carboline.

A solution of 7-chloro-8-methoxy-β-carboline (677 mg, 2.9 mmol) intrifluoroacetic acid (10 ml) was treated with NaNO₃ (260 mg, 3.06 mmol).The reaction was stirred for 3 h at RT and then concentrated. The crudeproduct was chromatographed on silica eluting with a 5% to 10% methanolin chloroform gradient to provide 463 mg of7-chloro-8-methoxy-9-nitro-β-carboline.

A solution of 7-chloro-8-methoxy-9-nitro-β-carboline (460 mg, 1.66 mmol)in EtOH (25 ml) was treated with SnCl₂-2H₂O (450 mg, 2.00 mmol). Thereaction was stirred for 5 h at 65° C. and then concentrated. The crudeproduct was chromatographed on silica eluting with a 5 to 10% methanolin chloroform gradient to provide 410 mg of7-chloro-8-methoxy-9-nitro-β-carboline.

A solution of 7-chloro-8-methoxy-9-nitro-β-carboline (21 mg, 0.085 mmol)in pyridine (1 ml) was treated with nicotinyl chloride hydrochloride (54mg, 0.30 mmol) and 4-dimethylaminopyridine (5 mg). After stirring at 95°C.-100° C. for 7 h the reaction was concentrated, the residue slurriedwith 10% Na₂CO₃, and then chromatographed on silica eluting with a 5% to10% methanol in chloroform gradient to provide 4.7 mg of the titlecompound.

EXAMPLE 82 N-(6-Chloro-9H-β-carbolin-8-yl)-3,4-difluoro-benzamide

To a cold (3° C.-5° C.) solution of 9-amino-7-chloro-β-carboline (2.50g, 11.5 mmol, as prepared in example 60 above) in pyridine (130 ml) wasadded 3,4-diflourobenzoyl chloride (1.67 ml, 13.25 mmol). The reactionwas allowed to warm to RT and stirred for 20 h before diluting thereaction with water (60 ml) and 1M NaOH (15 ml). After stirring for 3 hat RT, the pH of the mixture was adjusted to 8-9 with 1M HCl and thenpoured into water (250 ml). The mixture was allowed to stand for 30 minand the product was filtered to provide 3.95 g of the title compoundafter washing with water and drying under reduced pressure at 55° C.-60°C.

EXAMPLE 83 6-Chloro-N-(6-chloro-9H-β-carbolin-8-yl)-nicotinamide

To a cold (3-5° C.) solution of 9-amino-7-chloro-β-carboline (1.40 g,6.45 mmol, as prepared in example 60 above) in pyridine (72 ml) wasadded 6-chloro-nicotinyl chloride (1.30 g, 7.42 mmol). The reaction wasallowed to warm to RT and stirred for 16 h before diluting the reactionwith water (60 ml) and 1M NaOH (8 ml). After stirring for 40 min at RT,the mixture was poured into water (200 ml). The mixture was allowed tostand for 30 min and the product was filtered to provide 2.20 g of thetitle compound after washing with water and drying under reducedpressure at RT.

The examples in Table 1 show the structures of certain preparedcompounds, including those of the previous examples, and were preparedaccording to methods used in the previous examples. TABLE 1 ExampleStructure Empirical formula MS (M + H) 1

C₁₁H₇BrN₂ 248 2

C₁₃H₉BrN₂O 290 3

C₁₁H₇FN₂ 187 4

C₁₄H₁₅ClN₂ 211 5

C₁₂H₇N₃ 194 6

C₁₁H₈ClN₃O₂ 214 7

C₁₄H₉F₃N₂O₄ 213 8

C₁₁H₇Br₂ClN₂ 327 9

C₁₁H₆Cl₂N₂ 238 10

C₁₂H₉BrN₂O₂S 326 11

C₁₂H₉BrN₂ 262 12

C₁₁H₇ClN₂ 204 13

C₁₃H₉ClN₂O 246 14

C₁₁H₆ClN₃O₂ 249 15

C₁₁H₈ClN₃ 219 16

C₁₅H₁₁ClF₃N₃O₃ 261 17

C₁₆H₁₄BrN₃O₂ 361 18

C₁₅H₁₃ClN₂O₂ 290 19

C₁₃H₁₁ClN₂O 248 20

C₁₃H₉ClN₂O₂ 262 21

C₁₂H₁₀N₂O 199 22

C₁₃H₁₀ClN₃O 261 23

C₁₂H₁₀N₂O 199 24

C₁₂H₈Br₂N₂O 257 25

C₁₈H₂₀N₂O₃ 313 26

C₁₉H₁₆N₂O 289 27

C₁₄H₁₄N₂O 227 28

C₁₂H₉BrN₂ 262 29

C₁₄H₁₂N₂O₂ 241 30

C₁₂H₁₀N₂O 199 31

C₁₁H₇FN₂ 187 32

C₁₃H₁₁BrN₂O 292 33

C₁₁H₈N₂O 185 34

C₁₁H₆ClFN₂ 222 35

C₁₃H₁₂N₂O 213 36

348 37

382 38

254 39

282 40

222 41

253 42

237 43

347 44

361 45

411 46

389 47

437 48

388 49

454 50

448 51

404 52

467 53

467 54

391 55

416 56

C₁₉H₁₂ClF₃N₄O₃ 323 57

C₁₈H₁₇ClF₃N₃O₃ 302 58

C₁₆H₁₄Cl₂N₂O₂ 338 59

C₁₆H₁₃Cl₂N₃O₃ 367 60

C₁₉H₁₂ClF₃N₄O₃ 323 61

C₂₀H₁₂ClF₄N₃O₃ 340 62

C₂₀H₁₂ClF₄N₃O₃ 340 63

C₁₂H₉N₃O₃ 244 64

C₁₅H₁₂Cl₂N₂O 308 65

C₁₅H₁₃Cl₃N₂O 66

C₁₂H₉ClN₂O 234 67

C₁₂H₁₀ClN₃O 249 68

C₁₈H₁₃ClN₄O₂ 353 69

C₂₁H₁₄ClF₃N₄O₃ 349 70

C₁₃H₁₀Cl₂N₂O₂ 298 71

C₂₀H₁₆ClN₃O₃ 383 72

C₁₉H₁₁ClN₄O 348 73

C₁₉H₁₁ClN₄O 348 74

C₁₉H₁₁ClF₃N₃O 391 75

C₁₆H₁₀ClN₃O₂ 313 76

C₁₆H₁₀ClN₃OS 329 77

C₁₈H₁₁ClF₃N₃O₂ 395 78

C₂₀H₂₀ClN₅O 383 79

C₁₅H₉ClN₄O₂ 314 80

C₁₆H₁₁ClN₄O₂ 328 81

C₁₈H₁₂Cl₂N₂O 344 82

C₁₈H₁₀ClF₂N₃O 359 83

C₁₇H₁₀Cl₂N₄O 358 84

C₁₄H₁₂Cl₂N₂O 296 85

C₁₅H₁₄Cl₂N₂O 310 86

C₁₇H₁₂ClN₃OS 343 87

C₁₇H₁₁ClN₄O 323 88

C₁₆H₁₀ClN₅O 323 89

C₁₉H₁₂ClN₃O₃ 367 90

C₂₀H₁₆ClN₃O₂ 366 91

C₁₃H₈ClN₃O₂ 274 92

C₁₆H₁₄Cl₂N₂O 322 93

C₁₇H₁₉Cl₂N₃O 353 94

C₁₂H₈ClN₃O₃ 279 95

C₁₂H₁₀ClN₃O 248 96

C₁₈H₁₈Cl₂N₂O 350 97

C₁₈H₁₅Cl₃N₄O 337 98

C₁₅H₁₇Cl₃N₄O 290 99

C₁₆H₁₃ClN₄O₂ 330 100

C₁₉H₁₄ClN₃O₂ 353 101

C₁₃H₈Cl₂N₂O₂ 296 102

C₁₅H₁₀Cl₂N₂O₃ 338 103

C₁₆H₁₃ClN₄O₂ 330 104

C₁₇H₁₁ClN₄O₂ 340 105

C₂₀H₂₀ClN₅O 383 106

C₁₇H₁₄ClN₅O 341 107

C₂₆H₂₄ClN₅O 359 108

C₁₈H₁₃ClN₄O 338 109

C₁₇H₁₁ClN₄O₂ 340 110

C₁₇H₁₃ClN₄O₂ 342 111

C₁₆H₁₂ClN₃O₃ 331 112

C₁₇H₁₁ClFN₃O₂S 377 113

C₁₈H₁₁BrClN₃O 401 114

C₁₉H₁₃ClFN₃O₂ 371 115

C₁₇H₁₃Cl₃N₄O₂ 339 116

C₁₈H₁₁Cl₂N₃O 357 117

C₁₇H₁₆ClN₃O 314 118

C₁₈H₁₂Cl₂N₄O₂ 388 119

C₁₆H₁₁ClN₄O₃ 343 120

C₁₉H₁₂ClF₂N₃O₂ 390 121

C₁₇H₁₂ClN₅O 339Pharmacological ExamplesI_(k)B-Kinase ELISA

The in-vitro assay for detecting and measuring inhibition activityagainst IκBα-kinase complex by candidate pharmacological agents employsa biotinylated polypeptide spanning both Ser³² and Ser³⁶ of IκBα and aspecific antibody binding only to the phosphorylated form of thepolypeptide, being either monoclonal or polyclonal (such as thecommercially-available anti-phospho-serine³² IκBα antibodies from NewEngland Biolabs, Beverly, Mass., USA, cat. #9240). Once theantibody-phospho-polypeptide complex is formed, the complex can bedetected by a variety of analytical methods utilizing such asradioactivity, luminescence, fluorescence or optical absorbance. For theuse of the ELISA method, the complex can be immobilized either onto abiotin-binding plate (such as Neutravidin coated plate) and detectedwith a secondary antibody conjugated to HRP, or onto an antibody-bindingplate (such as Protein-A coated plate) and detected with biotin-bindingprotein conjugated to HRP (such as Streptavidin-HRP). The level ofactivity can be correlated with a standard curve using syntheticphosphopeptides corresponding to the substrate polypeptide.

Experimental

IκBα kinase complex was prepared by first diluting 10 mL of HeLa S3cell-extracts S100 fraction with 40 mL of 50 mM HEPES pH 7.5. Then, 40%ammonium sulfate was added and incubated on ice for 30 minutes.Precipitated pellet was redissolved with 5 mL of SEC buffer (50 mM HEPESpH 7.5, 1 mM DTT, 0.5 mM EDTA, 10 mM 2-glycerophosphate), clarified bycentrifugation at 20,000×g for 15 min., and filtration through a 0.22 μmfilter unit. Sample was loaded onto a 320-mL Superose-6 FPLC column(Amersham Pharmacia Biotech AB, Uppsala, Sweden) equilibrated with SECbuffer operated at 2 mL/min flow rate at 4° C. Fractions spanning the670-kDa molecular-weight marker were pooled for activation.Kinase-containing pool was then activated by incubating with 100 nMMEKK1Δ, 250 μM MgATP,

10 mM MgCl₂, 5 mM DTT, 10 mM 2-glycerophosphate, 2.5 μM Microcystin-LR,for 45 minutes at 37° C. Activated enzyme was stored at −80° C. untilfurther use. Per well of a 96-well plate, compounds at variousconcentrations in 2 μL DMSO were pre-incubated for 30 minutes at 25° C.with 43 μL of activated enzyme diluted [1:25] with assay buffer (50 mMHEPES pH 7.5, 5 mM DTT, 10 mM MgCl₂, 10 mM 2-glycerophosphate, 2.5 μMMicrocystin-LR). Five microliters of peptide substrate (biotin-(CH₂)₆—DRHDSGLDSMKD-CONH₂) at 200 μM stock solution was added to each well andincubated for 1 hour before quenching with 150 μL of 50 mM HEPES pH 7.5,0.1% BSA, 50 mM EDTA, plus [1:200] antibody. Quenched kinase reactionsamples and phospho-peptide-calibration standards (biotin-(CH₂)₆—DRHDS[PO₃]GLDSMKD-CONH₂, serially diluted in assay buffer) at 100 μL perwell were transferred to a Protein-A plate (Pierce Chemical Co.,Rockford, Ill., USA) and incubated for 2 hours. with shaking. Following3 washes with PBS, 100 μL of 0.5 μg/mL Streptavidin conjugated with HRP(horseradish peroxidase) diluted with 50 mM HEPES/0.1% BSA, was addedfor 30 minutes. After 5 washes with PBS,

100 μL TMB substrate (Kirkegaard & Perry Laboratories, Gaithersburg,Md., USA) was added and color development was stopped by adding 100 μLof 0.18 M H₂SO₄. Absorbance signals were recorded at 450 nm.Calibration-curve standards were fitted by linear regression using a4-parameter dose-response equation. Based on this standard curve, levelsof kinase activity were calculated in order to determine inhibitionactivity of candidate pharmacological agents.

Table 2 which follows shows the results. TABLE 2 Kinase inhibition at asubstance concentration of IC₅₀ in μM IkB- Example kinase number IC₅₀ 10.4 2 0.4 3 1 4 2.5 5 1 6 3 7 65 8 0.2 9 0.2 10 0.4 11 0.7 12 0.4 13 0.514 4 15 0.8 16 0.3 17 5 18 23 19 3 20 14 21 1.8 22 15 23 22 24 4.6 25 3126 12 27 4.5 28 11 29 40 30 5.2 31 3.3 32 4.6 33 1.5 34 1 35 3.5 36 1.437 0.15 38 11 39 0.1 40 2 41 2.2 42 0.8 43 1 44 2 45 8.3 46 0.3 47 0.648 4 49 0.22 50 10 51 0.6 52 0.6 53 1.4 54 0.7 55 0.8 56 0.27 57 4.3 580.33 59 3.2 60 0.052 61 0.94 62 0.38 63 1.3 64 0.11 65 0.10 66 0.7 670.5 68 0.16 69 3.0 70 0.36 71 3.0 72 0.58 73 0.4 74 3.8 75 0.29 76 0.977 4.4 78 2.3 79 0.18 80 0.31 81 0.25 82 0.15 83 0.06 84 0.1 85 0.2 860.7 87 0.75 88 0.28 89 0.57 90 1.4 91 2.3 92 0.4 93 1.3 94 0.64 95 1.096 1.3 97 0.69 98 0.9 99 0.09 100 1.5 101 1.8 102 0.8 103 0.31 104 1.0105 0.4 106 0.6 107 0.4 108 2.1 109 2.1 110 0.3 111 0.54 112 0.93 1130.64 114 2.1 115 4.6 116 1.8 117 0.67 118 0.12 119 0.6 120 0.4

The compound according to example 121 shows a IC₅₀ of 1.7.

Mouse Heterotopic Cardiac Transplant Model

In the mouse heterotopic cardiac transplant model across fullhistocompatibility barriers (BALB/c->C57BL/6 or B6/129), graft survivalis typically limited to 7.3±0.4 days (mean±SD, n0 allografts) (see forexample in Hancock W W, Sayegh M H, Zheng X G, Peach R, Linsley P S,Turka L A. Costimulatory function and expression of CD40-ligand, CD80and CD86 or in vascularized murine cardiac allograft rejection. ProcNatl Acad Sci (USA) 93, 1996, 13967-13972; and Hancock W W, Buelow R,Sayegh M H, Turka L A. Antibody-induced transplant arteriosclerosis isprevented by graft expression of anti-oxidant and anti-apoptotic genes.Nature Med 4, 1998, 1392-1396).

The effects of oral administration of the compounds according toexamples 49 and 60 were tested using 25 mg/kg/day for 14 days, startingat transplantation in said animal model. Whereas grafts in animalsreceiving the carrier, methyl-cellulose, rejected by 7 days (6.7±0.8),grafts in compound 49-treated mice survived around 15 days (15.3±0.6),and grafts in those given compound 60 survived for 20 days (20±1).Current immunosuppressive therapies used in transplantation have limitedefficacy and/or considerable toxicity. Targeting of IkB-kinase withthese agents significantly prolonged allograft survival withoutassociated toxicity.

1. A compound of formula I

or a stereoisomeric form of a compound of the formula I or aphysiologically tolerable salt of a compound of the formula I, where B₆,B₇, B₈ and B₉ are ring atoms independently chosen from carbon atoms andnitrogen atoms, where B₆, B₇, B₈ and B₉ together comprise no more thantwo nitrogen atoms; wherein in case a) the substituents R¹, R² and R³may be independently chosen from: 1.1. hydrogen atom, 1.2. halogen, 1.3.—CN, 1.4. —COOH, 1.5. —NO₂, 1.6. —NH₂, 1.7. —O—(C₁-C₁₀)-alkyl, whereinalkyl is unsubstituted or mono- to penta-substituted by substituentsindependently chosen from: 1.7.1 phenyl, which is unsubstituted or mono-to penta-substituted by substituents independently chosen from halogenor 4-(C₁-C₄)-alkyl, 1.7.2 halogen, 1.7.3 —NH₂, 1.7.4 —OH, 1.7.5 —COOR¹⁶,wherein R¹⁶ is hydrogen atom or —(C₁-C₁₀)-alkyl, 1.7.6 —NO₂, 1.7.7—S(O)—R¹⁴, wherein y is zero, 1 or 2, R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl,which phenyl is unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those defined under 1.7.1 to1.7.11, amino or —N(R¹³)₂, wherein R¹³ is independently of one anotherchosen from hydrogen atom, phenyl, —(C₁-C₁₀)-alkyl, —C(O)—(C₁-C₇)-alkyl,—C(O)-phenyl, —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,—C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R⁴ wherein R¹⁴ and y are as defined in1.7.7, and wherein the R¹³ alkyl or phenyl groups in each case areunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11, or R¹³together with the nitrogen atom to which it is bonded may beindependently chosen to form a heterocycle having 5 to 7 ring atoms,1.7.8 —O-phenyl, wherein phenyl is unsubstituted or mono- topenta-substituted independently of one another as defined under 1.7.1 to1.7.11, 1.7.9 a radical selected from pyrrolidine, tetrahydropyridine,piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine,pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine,2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene orthiomorpholine, 1.7.10 —(C₃-C₇)-cycloalkyl or 1.7.11=0, 1.8. —N(R¹³)₂,wherein R¹³ is as defined in 1.7.7 above, 1.9. —NH—C(O)—R⁵, wherein R¹⁵is 1.9.1 a radical selected from pyrrolidine, tetrahydropyridine,piperidine, piperazine, imidazoline, pyrazolidine, furan, morpholine,pyridine, pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine,2-isoxazoline, isothiazolidine, 2-isothiazoline, thiophene orthiomorpholine, wherein said radical is unsubstituted or mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above, by —CF₃, by benzyl or by—(C₁-C₁₀)-alkyl, wherein the —(C₁-C₁₀)-alkyl is mono to tri-substitutedby substituents independently chosen from those as defined under 1.7.1to 1.7.11 above, 1.9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstitutedor mono- to penta-substituted by substituents independently chosen fromthose as defined under 1.7.1 to 1.7.11 above or by —O—-(C₁-C₁₀)-alkyl,wherein alkyl is unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above, 1.9.3 —(C₃-C₇)-cycloalkyl, 1.9.4 —N(R³)₂, wherein R¹³ isas defined in 1.7.7 above, or 1.9.5 phenyl, wherein phenyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,by —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl, wherein alkylis mono to tri-substituted by substituents independently chosen fromthose as defined under 1.7.1 to 1.7.11 above, or by two substituents ofsaid phenyl which form a dioxolan ring, 1.10. —S(O)_(y)—R¹⁴, wherein R¹⁴and y are as defined in 1.7.7 above, 1.11. —C(O)—R¹², wherein R¹² isphenyl or —(C₁-C₇)-alkyl, wherein alkyl or phenyl are unsubstituted ormono- to penta-substituted by substituents independently chosen fromthose as defined under 1.7.1 to 1.7.11 above, 1.12. —C(O)—O—R¹², whereinR¹² is as defined in 1.11. above, 1.13. —(C₁-C₁₀)-alkyl, wherein alkylis unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,1.14. —O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl, 1.15.—O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl, 1.16. —(C₁-C₄)-alkyl-N(R¹³)₂,wherein R¹³ is as defined in 1.7.7 above 1.17. —CF₃ or 1.18. —CF₂—CF₃,R⁴ is
 1. —(C₁-C₁₀)-alkyl, wherein alkyl is mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above,
 2. —CF₃,
 3. —CF₂—CF₃,
 4. —CN,
 5. —S(O)_(y)—R¹⁴, whereinR¹⁴ and y are as defined in 1.7.7 above,
 6. —NH₂,
 7. —O—(C₁-C₁₀)-alkyl,wherein alkyl is mono- to penta-substituted by substituentsindependently chosen from 7.1 phenyl, which is unsubstituted or mono- topenta-substituted by substituents independently chosen from halogen or—O—(C₁-C₄)-alkyl, 7.2 halogen, 7.3 —NH₂, 7.4 —OH, 7.5 —COOR⁶, whereinR¹⁶ is hydrogen atom or —(C₁-C₁₀)-alkyl, 7.6 —NO₂, 7.7 —S(O)—R¹⁴,wherein y is zero, 1 or 2, R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenylis unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11, aminoor —N(R³)₂, wherein R¹³ is independently of one another chosen fromhydrogen atom, phenyl, —(C₁-C₁₀)-alkyl, —C(O)—(C₁-C₇)-alkyl,—C(O)-phenyl, —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,—C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R¹⁴, wherein R¹⁴ and y are defined asin 7.7 above, and wherein the R¹³ alkyl or phenyl groups in each caseare unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,or R¹³ together with the nitrogen atom to which it is bonded form aheterocycle having 5 to 7 ring atoms, 7.8 —O-phenyl, wherein phenyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,7.9 a radical selected from pyrrolidine, tetrahydropyridine, piperidine,piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine,pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, thiophene,2-isoxazoline, isothiazolidine, 2-isothiazoline, or thiomorpholine, 7.10—(C₃-C₇)-cycloalkyl or 7.11 ═O,
 8. —N(R¹⁷)₂, wherein R¹⁷ isindependently of one another chosen from hydrogen atom, phenyl,—(C₁-C₁₀)-alkyl, —C(O)-phenyl, —C(O)—NH—(C₁-C₇)-alkyl,—C(O)—(C₁-C₁₀)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,—C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R¹⁴ wherein R¹⁴ and y are as defined asin 7.7 above, and wherein alkyl or phenyl in each case are unsubstitutedor mono- to penta-substituted independently of one another as definedunder 1.7.1 to 1.7.11 above, or R¹⁷ together with the nitrogen atom towhich it is bonded form a heterocycle having 5 to 7 ring atoms, 9.—NH—C(O)—R¹⁵, wherein R¹⁵ is 9.1 a radical selected from pyrrolidine,tetrahydropyridine, piperidine, piperazine, imidazoline, pyrazolidine,furan, morpholine, pyridine, pyridazine, pyrazine, oxolan, imidazoline,isoxazolidine, 2-isoxazoline, isothiazolidine, 2-isothiazoline,thiophene or thiomorpholine, Wherein said radical is unsubstituted ormono- to penta-substituted by substituents independently chosen fromthose as defined under 1.7.1 to 1.7.11 above, —CF₃, benzyl or by—(C₁-C₁₀)-alkyl, wherein alkyl is mono to tri-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above, 9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above or by —O—(C₁-C₁₀)-alkyl, whereinalkyl is unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,9.3 —(C₃-C₇)-cycloalkyl, 9.4 —N(R¹³)₂, wherein R¹³ is as defined in1.7.7 above provided that —N(R¹³)₂ is not —NH₂, or 9.5 phenyl, whereinphenyl is unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,by —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl, wherein alkylis mono to tri-substituted by substituents independently chosen fromthose as defined under 1.7.1 to 1.7.11 above, or by two substituents ofthe phenyl radical which form a dioxolan ring
 10. —C(O)—R², wherein R¹²is phenyl or —(C₁-C₇)-alkyl, wherein phenyl or alkyl are mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above,
 11. —C(O)—O—R¹², wherein R¹² isphenyl or —(C₁-C₇)-alkyl, wherein phenyl or alkyl are mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above, 12.—O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl, 13.—O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl or
 14. —(C₁-C₄)-alkyl-N(R¹³)₂,wherein R¹³ is as defined in 1.7.7 above, R⁵ is
 1. a hydrogen atom, 2.—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.4 above,
 3. —C(O)—R⁹, wherein R⁹ is —NH₂,—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- topenta-substituted by substituents independently chosen from those asdefined under 7.1 to 7.4, or —N(R¹³)₂, wherein R¹³ is as defined in1.7.7 above, or
 4. —S(O)₂—R⁹, wherein R⁹ is as defined in 3 above, or R⁴and R⁵ together with the atom to which they are bonded form aheterocycle, or R³ and R⁵ together with the atom to which they arebonded form a heterocycle containing an additional oxygen atom in thering and R⁶, R⁷ and R⁸ independently of one another are chosen fromhydrogen atom or methyl, or in case b) the substituents R¹, R² and R⁴may be independently chosen as defined under 1.1 to 1.18 in case a)above, R³ is
 1. —CF₃,
 2. —CF₂—CF₃,
 3. —CN,
 4. —COOH,
 5. —NO₂,
 6. —NH₂,7. —O—(C₁-C₁₀)-alkyl, wherein alkyl is mono- to penta substituted bysubstituents independently chosen from 7.1 phenyl, which isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from halogen or —O—(C₁-C₄)-alkyl, 7.2 halogen, 7.3—NH₂, 7.4 —OH, 7.5 —COOR⁶, wherein R¹⁶ is hydrogen atom or—(C₁-C₁₀)-alkyl, 7.6 —NO₂, 7.7 —S(O)_(y)—R¹⁴, wherein y is zero, 1 or 2,R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenyl is unsubstituted or mono-to penta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11, amino or —N(R³)₂, wherein R¹³ isindependently of one another chosen from hydrogen atom, phenyl,—(C₁-C₁₀)-alkyl, —C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl,—C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,—C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R¹⁴, wherein R¹⁴ and y are defined asin 7.7 above, and wherein the R¹³ alkyl or phenyl groups in each caseare unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,or R¹³ together with the nitrogen atom to which it is bonded form aheterocycle having 5 to 7 ring atoms, 7.8 —O-phenyl, wherein phenyl isunsubstituted or mono- to penta- by substituents independently chosenfrom those as defined under 1.7.1 to 1.7.11 above, 7.9 a radicalselected from pyrrolidine, tetrahydropyridine, piperidine, piperazine,imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine,pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline,isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine, 7.10—(C₃-C₇)-cycloalkyl or 7.11 ═O,
 8. —N(R¹³)₂, wherein R¹³ is as definedin 1.7.7 above,
 9. —NH—C(O)—R¹⁵, wherein R¹⁵ is 9.1 a radical selectedfrom pyrrolidine, tetrahydropyridine, piperidine, piperazine,imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine,pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline,isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine, whereinsaid radical is unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above, —CF₃, benzyl or by —(C₁-C₁₀)-alkyl, wherein alkyl is monoto tri-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above, 9.2 —(C₁-C₁₀)-alkyl, wherein alkylis unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 aboveor by —O—-(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above, 9.3 —(C₃-C₇)-cycloalkyl, 9.4—N(R¹³)₂, wherein R¹³ is as defined in 1.7.7 above, or 9.5 phenyl,wherein phenyl is unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above, by —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃, by —(C₁-C₁₀)-alkyl,wherein alkyl is mono to tri-substituted by substituents independentlychosen from those as defined under 1.7.1 to 1.7.11 above, or by twosubstituents of the phenyl radical which form a dioxolan ring, 10.—S(O)_(y)—R¹⁴, wherein R¹⁴ and y are as defined in 1.7.7 above, 11.—C(O)—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein phenyl oralkyl are unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,12. —C(O)—O—R², wherein R¹² is phenyl or —(C—C₇)-alkyl, wherein phenylor alkyl are unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,13. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- topenta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11 above, 14.—O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl, 15.—O—(C₀-C₄)-alkyl-(C₃-C₇)-cycloalkyl or
 16. —(C₁-C₄)-alkyl-N(R¹³)₂,wherein R¹³ is as defined in 1.7.7 above, R⁵ is as defined as R⁵ in casea) above, R⁶, R⁷ and R⁸ independently of one another are chosen fromhydrogen atom or methyl.
 2. A compound of the formula I as claimed inclaim 1, wherein in case a) B₆, B₇, B₈, and B₉ are each a carbon atom,R¹, R² and R³ independently of one another are chosen from hydrogenatom, halogen, cyano, nitro, amino, —O—(C₁-C₇)-alkyl, wherein alkyl isunsubstituted or substituted by phenyl, —CF₂—CF₃, —CF₃, —N(R¹⁸)₂,wherein R¹⁸ is independently of one another chosen from hydrogen atom,—(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl, —C(O)-pyridyl, —C(O)—NH-phenyl,—C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or —C(O)—(C₁-C₇)-alkyl, whereinalkyl, pyridyl or phenyl are unsubstituted or mono- to tri-substitutedby substituents independently chosen from those as defined under 1.7.1to 1.7.11, or R¹⁸ together with the nitrogen atom to which it is bondedform a heterocycle having 5 to 7 ring atoms,  S(O)_(y)—R¹⁴, wherein y iszero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11, aminoor —N(R¹⁸)₂, wherein R¹⁸ is independently of one another chosen fromhydrogen atom, —(C₀-C₇)-alkyl, phenyl, —C(O)-phenyl, —C(O)-pyridyl,—C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or—C(O)—(C₁-C₇)-alkyl, wherein each alkyl is unsubstituted or mono- totri-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11, or R¹⁸ together with the nitrogen atom towhich it is bonded form a heterocycle having 5 to 7 ring atoms, or —C(O)—O—R₁, wherein R¹² is as defined as in 1.11 above, R⁴ is cyano,amino, —O—(C₁-C₇)-alkyl, wherein alkyl is substituted by phenyl;—CF₂—CF₃, —CF₃, —N(R¹⁸)₂, wherein R¹⁸ is independently of one anotherchosen from hydrogen atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl,—C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or—C(O)—(C₁-C₇)-alkyl, wherein each alkyl, pyridyl or phenyl areunsubstituted or mono- to tri-substituted independently of one anotheras defined under 1.7.1 to 1.7.11, or R¹⁸ together with the nitrogen atomto which it is bonded form a heterocycle having 5 to 7 ring atoms,S(O)_(y)—R¹⁴, wherein y is zero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl,phenyl, which phenyl is unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11, amino or —N(R¹⁸)₂, wherein R¹⁸ is independently of one anotherchosen from hydrogen atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl,—C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or—C(O)—(C₁-C₇)-alkyl, wherein each alkyl is unsubstituted or mono- totri-substituted independently of one another as defined under 1.7.1 to1.7.11, or R¹⁸ together with the nitrogen atom to which it is bondedform a heterocycle having 5 to 7 ring atoms, or —C(O)—O—R¹², wherein R¹²is phenyl or —(C₁-C₇)-alkyl, wherein said phenyl or alkyl areunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11 above,R⁶, R⁷ and R⁸ independently of one another are chosen from hydrogen atomor methyl, and R⁵ is as defined as for case a) above.
 3. A compound ofthe formula I as claimed in claim 1, wherein in case b) the substituentsR¹, R² and R⁴ independently of one another are hydrogen atom, halogen,cyano, nitro, amino, —O—(C₁-C₇)-alkyl, wherein alkyl is unsubstituted orsubstituted by phenyl, —CF₂—CF₃, —CF₃, —N(R¹⁸)₂, wherein R¹⁸ isindependently of one another chosen from hydrogen atom, —(C₁-C₇)-alkyl,phenyl, —C(O)-phenyl, —C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl,—C(O)—O—(C₁-C₄)-alkyl or —C(O)—(C₁-C₇)-alkyl, wherein each alkyl,pyridyl or phenyl are unsubstituted or mono- to tri-substitutedindependently of one another as defined under 1.7.1 to 1.7.11, or R¹⁸together with the nitrogen atom to which it is bonded form a heterocyclehaving 5 to 7 ring atoms, S(O)_(y)—R¹⁴, wherein y is zero, 1 or 2, andR¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenyl is unsubstituted or mono-to penta-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11, amino or —N(R¹⁸)₂, wherein R¹⁸ isindependently of one another chosen from hydrogen atom, —(C₁-C₇)-alkyl,phenyl, —C(O)-phenyl, —C(O)-pyridyl, —C(O)—N H-phenyl, —C(O)—O-phenyl,—C(O)—O—(C₁-C₄)-alkyl or —C(O)—(C₁-C₇)-alkyl, wherein each alkyl isunsubstituted or mono- to tri-substituted independently of one anotheras defined under 1.7.1 to 1.7.11, or R¹⁸ together with the nitrogen atomto which it is bonded form a heterocycle having 5 to 7 ring atoms, or—C(O)—O—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein saidphenyl or alkyl are unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above, R³ is cyano, nitro, amino, —O—(C₁-C₇)-alkyl, wherein alkylis substituted by phenyl, —CF₂—CF₃, —CF₃, —N(R¹⁸)₂, wherein R¹⁸ isindependently of one another chosen from hydrogen atom, —(C₁-C₇)-alkyl,phenyl, —C(O)-phenyl, —C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl,—C(O)—O—(C₁-C₄)-alkyl or —C(O)—(C₁-C₇)-alkyl, wherein each alkyl,pyridyl or phenyl are unsubstituted or mono- to tri-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11, or R¹⁸ together with the nitrogen atom to which it is bondedform a heterocycle having 5 to 7 ring atoms,  S(O)_(y)—R¹⁴, wherein y iszero, 1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 1.7.1 to 1.7.11, aminoor —N(R¹⁸)₂, wherein R¹⁸ is independently of one another chosen fromhydrogen atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl, —C(O)-pyridyl,—C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or—C(O)—(C₁-C₇)-alkyl, wherein each alkyl is unsubstituted or mono- totri-substituted by substituents independently chosen from those asdefined under 1.7.1 to 1.7.11, or R¹⁸ together with the nitrogen atom towhich it is bonded form a heterocycle having 5 to 7 ring atoms, or —C(O)—O—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein saidphenyl or alkyl are unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 1.7.1 to1.7.11 above, R⁶, R⁷ and R⁸ independently of one another are chosen fromhydrogen atom or methyl, and R⁵ is as defined in claim
 1. 4. A compoundof formula II

or a stereoisomeric form of a compound of the formula II or aphysiologically tolerable salt of a compound of the formula II, wherein;R¹ and R² are independently of one another chosen from hydrogen atom,halogen, cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃, —CF₂—CF₃,—S(O)_(y)—R, wherein y is 1 or 2, R¹⁴ is amino, —(C₁-C₇)-alkyl orphenyl, which phenyl is unsubstituted or mono- to tri-substituted asdefined for substituents under 1.7.1 to 1.7.11 in claim 1,  —N(R¹⁸)₂,wherein R¹⁸ is independently of one another chosen from hydrogen atom,—(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl, C(O)-pyridyl,—C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or—(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl or phenyl are unsubstituted ormono- to tri-substituted independently of one another as defined under1.7.1 to 1.7.11 in claim 1, or R¹⁸ together with nitrogen atom to whichit is bonded form a heterocycle having 5 to 7 ring atoms, R³ is cyano,amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃, —CF₂—CF₃, —S(O)_(y)—R¹⁴ wherein yis 1 or 2, R¹⁴ is amino, —(C₁-C₇)-alkyl or phenyl, which phenyl isunsubstituted or mono- to tri-substituted as defined for substituentsunder 1.7.1 to 1.7.11 in claim 1, —N(R⁸)₂, wherein R¹⁸ is independentlyof one another chosen from hydrogen atom,—(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl, —C(O)-pyridyl,—C(O)—O-phenyl, —C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O—(C₁-C₄)-alkyl or—(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl or phenyl are unsubstituted ormono- to tri-substituted by substituents independently chosen from thoseas defined under 1.7.1 to 1.7.11 in claim 1, or R¹⁸ together withnitrogen atom to which it is bonded form a heterocycle having 5 to 7ring atoms, and R⁵ is hydrogen atom, —(C₁-C₁₀)-alkyl, wherein alkyl isunsubstituted or mono- to tri-substituted by substituents independentlychosen from those as defined under 1.7.1 to 1.7.4 in claim 1, —C(O)—R⁹or —S(O)₂—R⁹, wherein R⁹ is —(C₁-C₁₀)-alkyl, —O—(C₁-C₁₀)-alkyl, whereinalkyl is unsubstituted or mono- to tri-substituted independently of oneanother as defined under 1.7.1 to 1.7.4 in claim 1, or phenyl, which isunsubstituted or mono- to tri-substituted as defined under 1.7.1 to1.7.11 in claim 1, or —N(R¹⁸)₂, wherein R¹⁸ is independently of oneanother chosen from hydrogen atom, —(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl,—C(O)-phenyl, C(O)-pyridyl, —C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O-phenyl,—C(O)—O—(C₁-C₄)-alkyl or —(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl orphenyl are unsubstituted or mono- to tri-substituted independently ofone another as defined under 1.7.1 in to 1.7.11 in claim 1, or R¹⁸together with nitrogen atom to which it is bonded form a heterocyclehaving 5 to 7 ring atoms.
 5. A compound of formula II as claimed inclaim 4, wherein R¹ is bromo, —CF₃ or chloro, R² is hydrogen atom orO—(C₁-C₂)-alkyl, R³ is —N(R¹⁸)₂, wherein R¹⁸ is independently of oneanother chosen from hydrogen atom, —N—C(O)-pyridyl, —C(O)-phenyl,—(C₁-C₇)-alkyl, —C(O)—(C₁-C₄)-alkyl or —C(O)—O—(C₁-C₄)-alkyl, whereinalkyl or phenyl are unsubstituted or mono- to tri-substituted bysubstituents independently chosen from halogen or —O—(C₁-C₂)-alkyl, andR⁵ is hydrogen atom, methyl or S(O)₂—CH₃.
 6. A compound of the formulaII as claimed in claim 4, wherein R¹ is chloro, R³ is —N—C(O)—CH₂—O—CH₃and R² and R⁵ are each hydrogen atom, or R¹ is chloro, R³ is—N—C(O)-pyridyl, wherein pyridyl is unsubstituted or substituted bychloro, R² is hydrogen atom or —CH₃ and R⁵ is hydrogen atom, or R¹ ischloro, R³ is —N—C(O)-phenyl, wherein phenyl is mono- or di-substitutedby fluoro and R² and R⁵ are each hydrogen atom.
 7. A process for thepreparation of a compound of the formula I as claimed in claim 1, whichcomprises reacting a compound of formula III

in which R¹, R², R³, R⁴, B₆, B₇, B₈ and B₉ are each as defined informula I, with a compound of the formula IV,

in the presence of a acid, to yield a compound of the formula V

which is reacted with hydrazine hydrate and later with R⁶CHO orformaldehyde (R⁶ is H) to give a compound of formula VI

and then oxidizing formula VI to give a compound of the formula VII,

where R¹ to R⁴, R⁶ to R⁸ and B₆ to B₉ are as defined in formula I, acompound of formula (I).
 8. A process according to claim 7, wherein acompound of the formula VII is reacted with a compound of the formulaVIIIY—R⁵  (VIII) where Y is halogen or —OH and R⁵ is as defined in formulaI, to give a compound of the formula I.
 9. A process according to claim7, which further comprises resolving a compound of the formula I formedby the process of claim 7, which on account of its chemical structureoccurs in enantiomeric forms, into the pure enantiomers by saltformation with enantiomerically pure acids or bases, chromatography onchiral stationary phases or derivatization by means of chiralenantiomerically pure compounds such as amino acids, separation of thediastereomers thus obtained, and removal of the chiral auxiliary groups.10. A process according to claim 8, which further comprises resolving acompound of the formula I formed by the process of claim 8, which onaccount of its chemical structure occurs in enantiomeric forms, into thepure enantiomers by salt formation with enantiomerically pure acids orbases, chromatography on chiral stationary phases or derivatization bymeans of chiral enantiomerically pure compounds such as amino acids,separation of the diastereomers thus obtained, and removal of the chiralauxiliary groups.
 11. A process according to claim 7, which furthercomprises isolating a compound of the formula I prepared by the processof claim 7, either in free form or, in the case of the presence ofacidic or basic groups, converting it into physiologically tolerablesalts.
 12. A process according to claim 8, which further comprisesisolating a compound of the formula I prepared by the process of claim8, either in free form or, in the case of the presence of acidic orbasic groups, converting it into physiologically tolerable salts.
 13. Aprocess according to claim 9, which further comprises isolating acompound of the formula I prepared by process 9, either in free form or,in the case of the presence of acidic or basic groups, converting itinto physiologically tolerable salts.
 14. A composition which comprisesan efficacious amount of at least one compound chosen from the compoundsof formula I as claimed in claim 1, a physiologically tolerable salt ofthe compounds of the formula I or an optionally stereoisomeric form ofthe compounds of the formula I, together with at least onepharmaceutically suitable and physiologically tolerable excipient,additive, active compound or auxiliary.
 15. A method for the productionof a compound for the prophylaxis or therapy of disorders in whosecourse an increased activity of I_(k)B kinase is involved, comprisingbringing into a suitable administration form at least one compoundchosen from a compound of formula I,

a stereoisomeric form of a compound of formula I or a physiologicallytolerable salt of a compound of formula I, wherein B₆, B₇, B₈ and B₉ arering atoms independently chosen from carbon atoms and nitrogen atoms andwherein B₆, B₇, B₈ and B₉ together are no more than two nitrogen atomsat the same time; where the substituents R¹, R², R³, R⁴ and R⁸ may beindependently chosen from
 1. hydrogen atom,
 2. halogen,
 3. —OH,
 4. —CN,5. sulfo,
 6. —NO₂,
 7. —NH₂,
 8. alkoxy,
 9. substituted amino, 10.—NH—C(O)—R¹⁵, wherein R¹⁵ is a heterocycle having 5 to 7 ring atoms, analkyl, an aryl, a substituted aryl or a substituted alkyl,
 11. —COOH,12. —O—R¹⁰, wherein R¹⁰ is alkyl, substituted alkyl or aryl, 13.—C(O)—R¹², wherein R¹² is alkyl, substituted alkyl or aryl, 14.—C(O)—O—R², wherein R¹² is alkyl, substituted alkyl or aryl,
 15. aryl,16. —O-aryl,
 17. substituted aryl,
 18. —O-substituted aryl,
 19. alkyl,20. substituted alkyl,
 21. —CF₃ or
 22. —CF₂—CF₃, provided that at leastone of R¹, R², R³, R⁴ and R⁸ is not a hydrogen atom, R⁵ is
 1. hydrogenatom,
 2. alkyl,
 3. alkyl radical, substituted at one or more positionsby one or more of the radicals, halogen, amino or hydroxyl,
 4. —C(O)—R⁹or
 5. —S(O)₂—R⁹, in which R⁹ is a) alkyl, b) alkyl radical, substitutedat one or more positions by one or more of the radicals, halogen, aminoor hydroxyl, c) aryl, d) aryl radical, substituted at one or morepositions by one or more of the radicals, halogen, amino, or hydroxyl,e) —NH₂, f) alkoxy or g) substituted amino, and R⁶ and R⁷ may beindependently chosen from
 1. hydrogen atom,
 2. halogen,
 3. —OH, 4.methyl,
 5. —O—(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono- totri-substituted by substituents independently chosen from 5.1 aryl, 5.2halogen, 5.3 —NO₂, 5.4 sulfo, 5.5 —COOH, 5.6 —NH₂, 5.7 —O—(C₁-C₄)-alkylor 5.8 —OH, or
 6. —N(R¹³)₂, wherein R¹³ is independently of one anotherchosen from hydrogen atom, aryl, —C(O)—(C₁-C₄)-alkyl or substituted arylor alkyl, wherein said —C(O)—(C₁-C₄)-alkyl is unsubstituted or mono- totri-substituted independently of one another as defined under 5.1 to5.8, or R¹³ together with the nitrogen atom to which it is bonded form aheterocycle having 5 to 7 ring atoms.
 16. The method as claimed in claim15, wherein B₆, B₇, B₈, and B₉ are each a carbon atom, R¹, R², R³, R⁴and R⁸ are independently chosen from
 1. hydrogen atom,
 2. halogen, 3.—CN,
 4. —COOH,
 5. —NO₂,
 6. —NH₂,
 7. —O—(C₁-C₁₀)-alkyl, wherein alkyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from 7.1 phenyl, which is unsubstituted or mono- topenta-substituted by substituents independently chosen from halogen or—O—(C₁-C₄)-alkyl, 7.2 halogen, 7.3 —NH₂, 7.4 —OH, 7.5 —COOR⁶, whereinR¹⁶ is hydogen atom or —(C₁-C₁₀)-alkyl, 7.6 —NO₂, 7.7 —S(O)—R¹⁴, whereiny is zero, 1 or 2, R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.11, amino or—N(R¹³)₂, wherein R¹³ is independently of one another chosen fromhydrogen atom, phenyl, —(C₁-C₁₀)-alkyl, —C(O)—(C₁-C₇)-alkyl,—C(O)-phenyl, —C(O)—NH—(C₁-C₇)-alkyl, —C(O)—O-phenyl, —C(O)—NH-phenyl,—C(O)—O—(C₁-C₇)-alkyl, —S(O)_(y)—R¹⁴ wherein R¹⁴ and y are as definedimmediately above, and wherein the R¹³ alkyl or phenyl groups in eachcase are unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.11 above, orR¹³ together with the nitrogen atom to which it is bonded form aheterocycle having 5 to 7 ring atoms, 7.8 —O-phenyl, wherein phenyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.11 above, 7.9a radical selected from pyrrolidine, tetrahydropyridine, piperidine,piperazine, imidazoline, pyrazolidine, furan, morpholine, pyridine,pyridazine, pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline,isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine, 7.10—(C₃-C₇)-cycloalkyl or 7.11 ═O,
 8. —N(R¹³)₂, wherein R¹³ is as definedin 7.7 above,
 9. —NH—C(O)—R¹⁵, wherein R¹⁵ is 9.1 a radical selectedfrom pyrrolidine, tetrahydropyridine, piperidine, piperazine,imidazoline, pyrazolidine, furan, morpholine, pyridine, pyridazine,pyrazine, oxolan, imidazoline, isoxazolidine, 2-isoxazoline,isothiazolidine, 2-isothiazoline, thiophene or thiomorpholine, whereinsaid radical is unsubstituted or mono- to penta-substituted bysubstituents independently chosen from those as defined under 7.1 to7.11 above, —CF₃, benzyl or by —(C₁-C₁₀)-alkyl, wherein alkyl is mono totri-substituted independently of one another as defined under 7.1 to7.11 above, 9.2 —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-to penta-substituted by substituents independently chosen from those asdefined under 7.1 to 7.11 above or by —O—(C₁-C₁₀)-alkyl, wherein alkylis unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.11 above, 9.3—(C₃-C₇)-cycloalkyl, 9.4 —N(R³)₂, wherein R¹³ is as defined in 7.7above, or 9.5 phenyl, wherein phenyl is unsubstituted or mono- topenta-substituted by substituents independently chosen from those asdefined under 7.1 to 7.11 above, by —O—(C₁-C₁₀)-alkyl, by —CN, by —CF₃,by —(C₁-C₁₀)-alkyl, wherein alkyl is mono to tri-substituted bysubstituents independently chosen from those as defined under 7.1 to7.11 above, or by two substituents of the phenyl radical which form adioxolan ring,
 10. —S(O)_(y)—R¹⁴, wherein R¹⁴ and y are as defined in7.7 above,
 11. —C(O)—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl,wherein phenyl or alkyl are unsubstituted or mono- to penta-substitutedby substituents independently chosen from those as defined under 7.1 to7.11 above,
 12. —C(O)—O—R¹², wherein R¹² is phenyl or —(C₁-C₇)-alkyl,wherein phenyl or alkyl are unsubstituted or mono- to penta-substitutedby substituents independently chosen from those as defined under 7.1 to7.11 above,
 13. —(C₁-C₁₀)-alkyl, wherein alkyl is unsubstituted or mono-to penta-substituted by substituents independently chosen from those asdefined under 7.1 to 7.11 above,
 14. —O—(C₁-C₆)-alkyl-O—(C₁-C₆)-alkyl,15. —O—(C₁-C₄)-alkyl-(C₃-C₇)-cycloalkyl,
 16. —(C₁-C₄)-alkyl-N(R¹³)₂,wherein R¹³ is as defined in 7.7 above
 17. —CF₃ or
 18. —CF₂—CF₃,provided that at least one of R¹, R², R³, R⁴ and R⁸ is not a hydrogenatom, R⁵ is
 1. hydrogen atom,
 2. —(C₁-C₁₀)-alkyl, wherein alkyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.4 above, 3.—C(O)—R⁹, wherein R⁹ is —NH₂, —(C₁-C₁₀)-alkyl, wherein alkyl isunsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.4, or—N(R¹³)₂, wherein R¹³ is as defined in 7.7 above, or
 4. —S(O)₂—R⁹,wherein R⁹ is as defined in 3 above, or R⁴ and R⁵ together with the atomto which they are bonded form a heterocycle, or R³ and R⁵ together withthe atom to which they are bonded form a heterocycle containing anadditional oxygen atom in the ring and R⁶ and R⁷ independently of oneanother are chosen from hydrogen atom or methyl.
 17. The method asclaimed in claim 16, wherein B₆, B₇, B₈, and B₉ are each a carbon atom,R¹, R², R³ and R⁴ independently of one another are hydrogen atom,halogen, cyano, nitro, amino, —O—(C₁-C₇)-alkyl, phenyl, —O-phenyl,—CF₂—CF₃, —CF₃, N(R¹³)₂, wherein R¹³ is independently of one anotherchosen from hydrogen atom, —(C₁-C₇)-alkyl, phenyl, —C(O)-phenyl,—C(O)-pyridyl, —C(O)—NH-phenyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl,—C(O)—(C₁-C₇)-alkyl or —(C₁-C₁₀)-alkyl, wherein alkyl, pyridyl or phenylare unsubstituted or mono- to tri-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.11 of claim16, or R¹³ together with nitrogen atom to which it is bonded form aheterocycle having 5 to 7 ring atoms,  —S(O)_(y)—R¹⁴, wherein y is zero,1 or 2, and R¹⁴ is —(C₁-C₁₀)-alkyl, phenyl, which phenyl isunsubstituted or mono- to penta-substituted as defined for substituentsunder 7.1 to 7.11 of claim 16, amino or —N(R³)₂, wherein R¹³ isindependently of one another chosen from hydrogen atom,—(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl, C(O)-pyridyl,—C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O-phenyl, —C(O)—O—(C₁-C₄)-alkyl or—(C₁-C₁₀)-alkyl, wherein each alkyl is unsubstituted or mono- totri-substituted independently of one another as defined under 7.1 to7.11 of claim 16, or R¹³ together with nitrogen atom to which it isbonded form a heterocycle having 5 to 7 ring atoms, or  —C(O)—O—R¹²,wherein R¹² is phenyl or —(C₁-C₇)-alkyl, wherein said phenyl or alkylare unsubstituted or mono- to penta-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.11 of claim16, R⁶, R⁷ and R⁸ independently of one another are hydrogen atom,methyl, amino, —N(R¹³)₂, wherein R¹³ is independently of one anotherchosen from hydrogen atom, —(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl,—C(O)-phenyl, C(O)-pyridyl, —C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O-phenyl,—C(O)—O—(C₁-C₄)-alkyl or —(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl orphenyl are unsubstituted or mono- to tri-substituted independently ofone another as defined under 7.1 to 7.11 of claim 16, or R¹³ togetherwith nitrogen atom to which it is bonded form a heterocycle having 5 to7 ring atoms, provided that at least one of R¹, R², R³, R⁴ and R⁸ is nota hydrogen atom, and R⁵ is as defined in claim
 16. 18. A method for theproduction of a compound for the prophylaxis or therapy of disorders inwhose course an increased activity of IkB kinase is involved, comprisingbringing into a suitable administration form at least one compoundchosen from a compound of formula II,

a stereoisomeric form of a compound of the formula II, or aphysiologically tolerable salt of a compound of the formula II, wherein,R¹, R² and R³ are independently chosen from hydrogen atom, halogen,cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃, —CF₂—CF₃, —S(O)_(y)—R¹⁴wherein y is 1 or 2, R¹⁴ is amino, —(C₁-C₇)-alkyl, phenyl, which isunsubstituted or mono- to tri-substituted by substituents, independentlychosen from those as defined under 7.1 to 7.9 of claim 16, or —N(R¹³)₂,wherein R¹³ is independently of one another chosen from hydrogen atom,—(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl, —C(O)-phenyl, —C(O)—O-phenyl,—C(O)-pyridyl, —C(O)—NH—(C₁-C₄)-alkyl, —C(O)—O—(C₁-C₄)-alkyl, or—(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl or phenyl are unsubstituted ormono- to tri-substituted with substitutents independently chosen fromthose as defined under 7.1 to 7.11 of claim 16, or R¹³ together with thenitrogen atom to which it is bonded form a heterocycle having 5 to 7ring atoms, provided that at least one of R¹, R² and R³ is not ahydrogen atom, and R⁵ is hydrogen atom, —(C₁-C₁₀)-alkyl, wherein alkylis unsubstituted or mono- to tri-substituted by substituentsindependently chosen from those as defined under 7.1 to 7.4 of claim 16,—C(O)—R⁹ or —S(O)₂—R⁹, wherein R⁹ is —(C₁-C₁₀)-alkyl, —O—(C₁-C₁₀)-alkyl,wherein alkyl is unsubstituted or mono- to tri-substituted bysubstituents independently chosen from those as defined under 7.1 to 7.4of claim 16, phenyl, which is unsubstituted or mono- to tri-substitutedby substituents independently chosen from those as defined under 7.1 to7.11 of claim 16, or —N(R¹³)₂, wherein R¹³ is independently of oneanother chosen from hydrogen atom, —(C₁-C₇)-alkyl-C(O)—(C₁-C₇)-alkyl,—C(O)-phenyl, —C(O)—O-phenyl, —C(O)-pyridyl, —C(O)—NH—(C₁-C₄)-alkyl,—C(O)—O—(C₁-C₄)-alkyl, or —(C₁-C₁₀)-alkyl, wherein pyridyl, alkyl orphenyl are unsubstituted or mono- to tri-substituted with substitutentsindependently chosen from those as defined under 7.1 to 7.11 of claim16, or R¹³ together with the nitrogen atom to which it is bonded form aheterocycle having 5 to 7 ring atoms.
 19. The method as claimed in claim18, wherein R¹, R² and R³ are independently chosen from hydrogen atom,halogen, cyano, amino, —O—(C₁-C₄)-alkyl, nitro, —CF₃ or N(R¹³)₂, whereinR¹³ is independently of one another chosen from hydrogen atom,—(C₁-C₇)-alkyl, —C(O)—(C₁-C₇)-alkyl, —C(O)-pyridyl, —C(O)-phenyl or—C(O)—O—(C₁-C₄)-alkyl, wherein alkyl or phenyl are unsubstituted ormono- to tri-substituted by substituents independently chosen fromhalogen or —O—(C₁-C₄)-alkyl, and R⁵ is hydrogen atom, —C(O)—CH₃—,methyl, —(O)₂—CH₃, —C(O)-morpholinyl, —CH₂—CH₂—OH or —CH₂—C(O)—NH₂,provided that no more than two of R¹, R², R³ and R⁵ are a hydrogen atom.20. The method as claimed in claim 18, wherein R¹ is bromo, —CF₃ orchloro, R² is hydrogen atom or O—(C₁-C₂)-alkyl, R³ is hydrogen atom,bromo, chloro or —N(R¹³)₂, wherein R¹³ is independently of one anotherchosen from hydrogen atom, —C(O)-phenyl, —(C₁-C₇)-alkyl,—C(O)—(C₁-C₄)-alkyl or —C(O)—O—(C₁-C₄)-alkyl, wherein alkyl or phenylare unsubstituted or mono- to tri-substituted by substituentsindependently chosen from halogen or —O—(C₁-C₂)-alkyl, and R⁵ ishydrogen atom, —C(O)—CH₃—, methyl or —S(O)₂—CH₃, provided that no morethan two of R¹, R², R³ and R⁵ are a hydrogen atom.
 21. The method asclaimed in claim 18, wherein R¹ is chloro, R³ is —N—C(O)—CH₂—O—CH₃ andR² and R⁵ are each hydrogen atom, or R¹ is chloro, R³ is—N—C(O)-pyridyl, wherein pyridyl is unsubstituted or substituted bychloro, R² is hydrogen atom or —O—CH₃ and R⁵ is hydrogen atom, or R¹ ischloro, R³ is —N—C(O)-phenyl, wherein phenyl is mono- or di-substitutedby fluoro and R² and R⁵ are each hydrogen atom, or R¹ and R³ are eachchloro, R² is —C(O)—CH₃ and R⁵ is hydrogen atom, or R¹ and R³ are eachchloro, R² is —C(O)—CH₂—CH₃ and R⁵ is hydrogen atom.
 22. A method fortreating a patient experiencing at least one disorder involving anincreased activity of I_(k)B kinase, the method comprising administeringto the patient an efficacious amount of at least one compound chosenfrom a compound of formula I as set forth in claim 1, a stereoisomericform of a compound of the formula I, or a physiologically tolerable saltof a compound of the formula I.
 23. The method as claimed in claim 22,wherein the at least one disorder is joint inflammation, acutesynovitis, tuberculosis, atherosclerosis, muscle degeneration, cachexia,Reiter's syndrome, endotoxaemia, sepsis, septic shock, endotoxic shock,gram negative sepsis, gout, toxic shock syndrome chronic pulmonaryinflammatory diseases, silicosis, pulmonary sarcoidosis, bone resorptiondiseases, reperfusion injury, carcinoses, leukemia, sarcomas, lymph nodetumors, skin carcinoses, lymphoma, apoptosis, graft versus hostreaction, allograft rejection, leprosy, infections, acquired immunedeficiency syndrome (AIDS); AIDS related complex; cachexia secondary toinfection or malignancy; cachexia secondary to acquired immunedeficiency syndrome or to cancer; keloid and scar tissue formation;pyresis; diabetes; inflammatory bowel diseases; diseases of or injury tothe brain in which over-expression of TNFα has been implicated,psoriasis, Alzheimer's disease, carcinomatous disorders (potentiation ofcytotoxic therapies), cardiac infarct, chronic obstructive pulmonarydisease and acute respiratory distress syndrome.
 24. The method asclaimed in claim 22, wherein the disorder is joint inflammationincluding arthritis and arthritic conditions.
 25. The method as claimedin claim 24, wherein the disorder is arthritis or arthritic conditionschosen from rheumatoid arthritis, rheumatoid spondylitis, goutyarthritis, traumatic arthritis, rubella arthritis, psoriatic arthritis,and osteoarthritis.
 26. The method of claim 22, wherein the disorder ischronic pulmonary inflammatory diseases chosen from asthma and adultrespiratory distress syndrome.
 27. The method of claim 22, wherein thedisorder is an infection chosen from viral infections, parasiticinfections, and yeast and fungal infections.
 28. The method of claim 27,wherein the disorder is a viral infection chosen from HIV,cytomegalovirus, influenza, adenovirus and the Herpes group of viruses.29. The method of claim 22, wherein the disorder is malaria.
 30. Themethod of claim 29, wherein the malaria is cerebral malaria.
 31. Themethod of claim 22, wherein the disorder is a yeast or fungal infectionincluding fungal meningitis; fever and myalgias due to infection. 32.The method of claim 22, wherein the the disorder is inflammatory boweldisease including Crohn's disease and ulcerative colitis.
 33. The methodof claim 22, wherein the the disorder is a disease of or injury to thebrain including multiple sclerosis or head trauma.
 34. A method fortreating a patient experiencing at least one disorder, the methodcomprising administering to the patient an efficacious amount of atleast one compound chosen from a compound of formula II as set forth inclaim 4, a stereoisomeric form of a compound of the formula II, or aphysiologically tolerable salt of a compound of the formula II, whereinthe at least one disorder is asthma, osteoarthritis, rheumatoidarthritis, Alzheimer's disease, carcinomatous disorders and cardiacinfarct.